Section 1 Synthetic Section

**3**

**Chapter 1**

**1. Introduction**

Introductory Chapter: Synthesis

and Antimicrobial Activities

*B.P. Nandeshwarappa, G.K. Prakash and S.O. Sadashiv*

Literature survey reveals that sulfur- and selenium-containing molecules have attracted great importance in synthetic organic chemistry; particularly, aromatic fiveand six-membered heterocycles fused or bridged to quinoline ring in linear fashion are found in many natural products due to their great pharmacological importance [1–7]. Substituted 2-azetidinone is an important class of compound for its importance in β-lactam antibiotic synthesis [8–10]. β-Lactam drugs in heterocycles are still the most widely prescribed antibiotics used in medicine [11]. The discovery of penicillin 2-azetidinone-based heterocycles have been one of the main classes of drugs with wide therapeutic activities, viz. anticonvulsant [12], anti-inflammatory [13], antibacterial [14], herbicidal [15], and also functioning as enzyme inhibitor [16]

The conversion of aryl quinolines into dihydroazeto[2′,3′:4,5]seleno[2,3-*b*]quinolines is of vital importance in synthetic organic chemistry. Seleno[2,3-*b*]quinolines are prepared via their corresponding halogenated derivatives. In the current approach, we have planned to synthesize title compounds by efficient methods for the synthesis of seleno[2,3-*b*]quinolines, starting from easily accessible dichloro substituents by a reaction with sodium hydrogen selenide in water media with quantitative yield under remarkably soft conditions. Also, we came to know that good results were achieved using sodium hydrogen selenide (NaHSe). Here, we wish to examine the feasibility and efficiency of an approach to synthesis of some new seleno[2,3-*b*]quinolines. In continuation of our research program directed toward the studies on Sulfur Chemistry [17–30] and synthesis of new potentially bioactive molecules, we were in need of a medicinal, bioorganic, industrial, cost-effective and commercial method for the synthesis of quinoline-based sulfur and selenium compounds. Also, the extensive biological properties and pharmaceutical applications have attracted interests in development of such sulfur and selenium-containing analogs.

In this contribution, we focused our attention on the fast and efficient synthesis of dihydroazeto[2′,3′:4,5]seleno[2,3-*b*]quinolines. At first, the key intermediate 3-formyl-2-chloroquinoline [31] and azitidones [32] have been prepared from avail-

of Dihydroazeto[2′,3′:4,5]

seleno[2,3-*b*]quinolines

and are effective on central nervous system.

**2. Results and discussions**

able reported methods.

#### **Chapter 1**

## Introductory Chapter: Synthesis and Antimicrobial Activities of Dihydroazeto[2′,3′:4,5] seleno[2,3-*b*]quinolines

*B.P. Nandeshwarappa, G.K. Prakash and S.O. Sadashiv*

#### **1. Introduction**

Literature survey reveals that sulfur- and selenium-containing molecules have attracted great importance in synthetic organic chemistry; particularly, aromatic fiveand six-membered heterocycles fused or bridged to quinoline ring in linear fashion are found in many natural products due to their great pharmacological importance [1–7].

Substituted 2-azetidinone is an important class of compound for its importance in β-lactam antibiotic synthesis [8–10]. β-Lactam drugs in heterocycles are still the most widely prescribed antibiotics used in medicine [11]. The discovery of penicillin 2-azetidinone-based heterocycles have been one of the main classes of drugs with wide therapeutic activities, viz. anticonvulsant [12], anti-inflammatory [13], antibacterial [14], herbicidal [15], and also functioning as enzyme inhibitor [16] and are effective on central nervous system.

The conversion of aryl quinolines into dihydroazeto[2′,3′:4,5]seleno[2,3-*b*]quinolines is of vital importance in synthetic organic chemistry. Seleno[2,3-*b*]quinolines are prepared via their corresponding halogenated derivatives. In the current approach, we have planned to synthesize title compounds by efficient methods for the synthesis of seleno[2,3-*b*]quinolines, starting from easily accessible dichloro substituents by a reaction with sodium hydrogen selenide in water media with quantitative yield under remarkably soft conditions. Also, we came to know that good results were achieved using sodium hydrogen selenide (NaHSe). Here, we wish to examine the feasibility and efficiency of an approach to synthesis of some new seleno[2,3-*b*]quinolines.

In continuation of our research program directed toward the studies on Sulfur Chemistry [17–30] and synthesis of new potentially bioactive molecules, we were in need of a medicinal, bioorganic, industrial, cost-effective and commercial method for the synthesis of quinoline-based sulfur and selenium compounds. Also, the extensive biological properties and pharmaceutical applications have attracted interests in development of such sulfur and selenium-containing analogs.

#### **2. Results and discussions**

In this contribution, we focused our attention on the fast and efficient synthesis of dihydroazeto[2′,3′:4,5]seleno[2,3-*b*]quinolines. At first, the key intermediate 3-formyl-2-chloroquinoline [31] and azitidones [32] have been prepared from available reported methods.

In the current investigation very interesting result was observed in the reaction of **1a–e** on subjected to ring cyclisation with sodium hydrogen selenide in water offered seleno quinolines **2a**–**e**. As expected, the 1 H NMR spectrum exhibited two peaks at δ 5.71 ppm and δ 4.91 ppm of two protons present in azetidinone ring, i.e., -N-CH-C- and -Se-CH- of newly formed thieno ring. The aromatic protons resonate as multiplets at δ 7.26–8.50 ppm. The structure was further confirmed by recording its mass spectra. It gave the molecular ion peak at m/z 351(M+ ) which corresponds to molecular formula C18H12N2OSe. Also, halogen test was used to confirm the absence of chlorine.

#### **3. Experimental**

IR spectra were taken on a Perkin Elmer 157 Infrared spectrophotometer. 1 H NMR spectra (300 MHz) were recorded on a Bruker supercon FT-NMR instrument using TMS as internal standard and mass spectra on a Jeol JMS-D 300 mass spectrometer operating at 70 eV. Melting points were determined in open capillary and are uncorrected. Purity of the compounds was checked by TLC on silica gel and the compounds were purified by column chromatography.

#### **3.1 Preparation of sodium hydrogen selenide**

A mixture of 1 g of selenium powder and 25 ml of water was taken in a 500 ml beaker. The heat obtained was controlled by keeping this mixture at ice cold condition. A calculated amount of sodium borohydride of 0.026 moles was added in stepwise with constant stirring. During this, immediate liberation of foaming takes place because of the formation of hydrogen gas. Once the addition of sodium borohydride is over, approximately 25 ml of water was added along the side of the beaker and stirring was continued over 15 min. During this, a colorless, deep, reddish NaHSe formed and thus the obtained result was used without further any purification.

#### **3.2 Preparation of dihydroazeto[2′,3′:4,5]seleno[2,3-***b***]quinolines (2a: E)**

About 0.01 mole of azitidone **1a**, and 0.01 mole sodium hydrogen selenide, and 50 ml of water were taken in a 500-ml round-bottom flask. The contents of the flask were refluxed over 10–15 min on a water bath. The crystalline solid **2a** was precipitated in the flask. The contents of the flask was poured into a beaker containing 500 mL ice cold water, stirred, filtered, and finally, washed with ethanol. The compound obtained was dried, and recrystallized from ethyl acetate. In the same way the compounds, **2b–e** were prepared (**Figure 1**).

**2a.** 1-Phenyl-2a, 7b-dihydroazeto[2′,3′:4,5]seleno[2,3-*b*]quinoline

Solid, mp. 280°C; 1 H NMR (300 MHz, DMSO-*d*6) *δ* (ppm): 4.91 (1H, s, -Se-CH-), 5.71 (1H, s, -N-CH-C), 7.26–8.50 (10H, m, Ar-H); IR (KBr) *ν* (cm<sup>−</sup><sup>1</sup> ): 1735.81 (C=O azetidinone), 1653. [M+], 351. Calcd. (%) for C18H12N2OSe: C; 61.55, H; 3.44, N; 7.98, Se; 22.48, Found: C; 61.08, H; 3.44, N; 7.95, Se; 22.43.

**2b.** 1-(4-Methylphenyl)-2a,7b-dihydroazeto[2′,3′:4,5]seleno[2,3-*b*]quinoline Solid, mp. 272°C; 1 H NMR (300 MHz, DMSO-*d*6) *δ* (ppm): 2.60 (s, -CH3), 4.87 (1H, s, -Se-CH-), 5.89 (1H, s, -N-CH-C), 7.20–8.49 (9H, m, Ar-H); IR (KBr) *ν* (cm<sup>−</sup><sup>1</sup> ): 1735.61 (C=O azetidinone), [M+], 365. Calcd. (%) for C19H14N2OSe: C; 62.47, H; 3.86, N; 7.67, Se; 21.62, Found: C; 62.45, H; 3.83, N; 7.64, Se; 21.65. **2c**. 1-(4-Methoxyphenyl)-2a,7b-dihydroazeto[2′,3′:4,5]seleno[2,3-*b*]quinoline

**5**

*Introductory Chapter: Synthesis and Antimicrobial Activities of Dihydroazeto[2′,3′:4,5]…*

H NMR (300 MHz, DMSO-*d*6) *δ* (ppm): 3.90 (s, -OCH3),

H NMR (300 MHz, DMSO-*d*6) *δ* (ppm): 4.79 (1H, s, -Se-

H NMR (300 MHz, DMSO-*d*6) *δ* (ppm): 4.70 (1H, s, -Se-

4.92 (1H, s, -Se-CH-), 5.79 (1H, s, -N-CH-C), 7.23–8.42 (9H, m, Ar-H); [M+], 381. Calcd. (%) for C19H14N2O2Se: C; 59.85, H; 3.70, N; 7.35, Se; 20.71. Found: C; 59.87, H;

*General synthetic procedure for dihydroazeto[2*′*,3*′*:4,5]seleno[2,3-*b*]quinolines.*

**2d.** 1-(4-Chlorophenyl)-2a,7b-dihydroazeto[2′,3′:4,5]seleno[2,3-*b*]quinoline

CH-), 5.70 (1H, s, -N-CH-C), 7.29–8.55 (9H, m, Ar-H); [M+], 385. Calcd. (%) for C18H11ClN2OSe: C; 56.05, H; 2.87, N; 7.26, Se; 20.47, Found: C; 56.09, H; 2.89, N; 7.23,

**2e.** 1-(4-Nitrophenyl)-2a,7b-dihydroazeto[2′,3′:4,5]seleno[2,3-*b*]quinoline

CH-), 5.68 (1H, s, -N-CH-C), 7.34–8.60 (9H, m, Ar-H). [M+], 396. Calcd. (%) for C18H11N3O3Se: C; 54.56, H; 2.80, N; 10.60, Se; 19.93, Found: C; 54.52, H; 2.83, N;

The in vitro antimicrobial activity was carried out against 24 h old cultures of three bacteria by disk diffusion method [33] using ampicillin as the reference. Compounds **2a**–**e** were tested against Gram-positive bacteria (*Staphylococcus aureus, Micrococcus roseus*) and Gram-negative bacteria (*Escherichia coli*). The compounds were tested at a concentration of 0.001 mol/ml in DMF against all organisms. The zone of inhibition was compared with the standard drug after 24 h of incubation at 25°C and measured in mm. Results are reported in **Table 1**, and it was found that compounds **2d** and **2e** were highly active against *S. aureus* and *M. roseus*

*DOI: http://dx.doi.org/10.5772/intechopen.92030*

Solid, mp. 287°C; 1

3.73, N; 7.39, Se; 20.73.

Se; 20.43.

**Figure 1.**

10.63, Se; 19.95.

Solid, mp. 292°C; <sup>1</sup>

Solid, mp. 288°C; <sup>1</sup>

**4. Antimicrobial activity**

*Introductory Chapter: Synthesis and Antimicrobial Activities of Dihydroazeto[2′,3′:4,5]… DOI: http://dx.doi.org/10.5772/intechopen.92030*

#### **Figure 1.**

*Heterocycles - Synthesis and Biological Activities*

absence of chlorine.

**3. Experimental**

purification.

Solid, mp. 280°C; 1

Solid, mp. 272°C; 1

offered seleno quinolines **2a**–**e**. As expected, the 1

its mass spectra. It gave the molecular ion peak at m/z 351(M+

compounds were purified by column chromatography.

way the compounds, **2b–e** were prepared (**Figure 1**).

N; 7.98, Se; 22.48, Found: C; 61.08, H; 3.44, N; 7.95, Se; 22.43.

**3.1 Preparation of sodium hydrogen selenide**

In the current investigation very interesting result was observed in the reaction of **1a–e** on subjected to ring cyclisation with sodium hydrogen selenide in water

peaks at δ 5.71 ppm and δ 4.91 ppm of two protons present in azetidinone ring, i.e., -N-CH-C- and -Se-CH- of newly formed thieno ring. The aromatic protons resonate as multiplets at δ 7.26–8.50 ppm. The structure was further confirmed by recording

to molecular formula C18H12N2OSe. Also, halogen test was used to confirm the

IR spectra were taken on a Perkin Elmer 157 Infrared spectrophotometer. 1

NMR spectra (300 MHz) were recorded on a Bruker supercon FT-NMR instrument using TMS as internal standard and mass spectra on a Jeol JMS-D 300 mass spectrometer operating at 70 eV. Melting points were determined in open capillary and are uncorrected. Purity of the compounds was checked by TLC on silica gel and the

A mixture of 1 g of selenium powder and 25 ml of water was taken in a 500 ml

beaker. The heat obtained was controlled by keeping this mixture at ice cold condition. A calculated amount of sodium borohydride of 0.026 moles was added in stepwise with constant stirring. During this, immediate liberation of foaming takes place because of the formation of hydrogen gas. Once the addition of sodium borohydride is over, approximately 25 ml of water was added along the side of the beaker and stirring was continued over 15 min. During this, a colorless, deep, reddish NaHSe formed and thus the obtained result was used without further any

**3.2 Preparation of dihydroazeto[2′,3′:4,5]seleno[2,3-***b***]quinolines (2a: E)**

**2a.** 1-Phenyl-2a, 7b-dihydroazeto[2′,3′:4,5]seleno[2,3-*b*]quinoline

CH-), 5.71 (1H, s, -N-CH-C), 7.26–8.50 (10H, m, Ar-H); IR (KBr) *ν* (cm<sup>−</sup><sup>1</sup>

(C=O azetidinone), 1653. [M+], 351. Calcd. (%) for C18H12N2OSe: C; 61.55, H; 3.44,

**2b.** 1-(4-Methylphenyl)-2a,7b-dihydroazeto[2′,3′:4,5]seleno[2,3-*b*]quinoline

): 1735.61 (C=O azetidinone), [M+], 365. Calcd. (%) for C19H14N2OSe: C;

**2c**. 1-(4-Methoxyphenyl)-2a,7b-dihydroazeto[2′,3′:4,5]seleno[2,3-*b*]quinoline

4.87 (1H, s, -Se-CH-), 5.89 (1H, s, -N-CH-C), 7.20–8.49 (9H, m, Ar-H); IR (KBr)

62.47, H; 3.86, N; 7.67, Se; 21.62, Found: C; 62.45, H; 3.83, N; 7.64, Se; 21.65.

About 0.01 mole of azitidone **1a**, and 0.01 mole sodium hydrogen selenide, and 50 ml of water were taken in a 500-ml round-bottom flask. The contents of the flask were refluxed over 10–15 min on a water bath. The crystalline solid **2a** was precipitated in the flask. The contents of the flask was poured into a beaker containing 500 mL ice cold water, stirred, filtered, and finally, washed with ethanol. The compound obtained was dried, and recrystallized from ethyl acetate. In the same

H NMR (300 MHz, DMSO-*d*6) *δ* (ppm): 4.91 (1H, s, -Se-

H NMR (300 MHz, DMSO-*d*6) *δ* (ppm): 2.60 (s, -CH3),

H NMR spectrum exhibited two

) which corresponds

H

): 1735.81

**4**

*ν* (cm<sup>−</sup><sup>1</sup>

*General synthetic procedure for dihydroazeto[2*′*,3*′*:4,5]seleno[2,3-*b*]quinolines.*

Solid, mp. 287°C; <sup>1</sup> H NMR (300 MHz, DMSO-*d*6) *δ* (ppm): 3.90 (s, -OCH3), 4.92 (1H, s, -Se-CH-), 5.79 (1H, s, -N-CH-C), 7.23–8.42 (9H, m, Ar-H); [M+], 381. Calcd. (%) for C19H14N2O2Se: C; 59.85, H; 3.70, N; 7.35, Se; 20.71. Found: C; 59.87, H; 3.73, N; 7.39, Se; 20.73.

**2d.** 1-(4-Chlorophenyl)-2a,7b-dihydroazeto[2′,3′:4,5]seleno[2,3-*b*]quinoline Solid, mp. 292°C; <sup>1</sup> H NMR (300 MHz, DMSO-*d*6) *δ* (ppm): 4.79 (1H, s, -Se-CH-), 5.70 (1H, s, -N-CH-C), 7.29–8.55 (9H, m, Ar-H); [M+], 385. Calcd. (%) for C18H11ClN2OSe: C; 56.05, H; 2.87, N; 7.26, Se; 20.47, Found: C; 56.09, H; 2.89, N; 7.23, Se; 20.43.

**2e.** 1-(4-Nitrophenyl)-2a,7b-dihydroazeto[2′,3′:4,5]seleno[2,3-*b*]quinoline Solid, mp. 288°C; <sup>1</sup> H NMR (300 MHz, DMSO-*d*6) *δ* (ppm): 4.70 (1H, s, -Se-CH-), 5.68 (1H, s, -N-CH-C), 7.34–8.60 (9H, m, Ar-H). [M+], 396. Calcd. (%) for C18H11N3O3Se: C; 54.56, H; 2.80, N; 10.60, Se; 19.93, Found: C; 54.52, H; 2.83, N; 10.63, Se; 19.95.

#### **4. Antimicrobial activity**

The in vitro antimicrobial activity was carried out against 24 h old cultures of three bacteria by disk diffusion method [33] using ampicillin as the reference. Compounds **2a**–**e** were tested against Gram-positive bacteria (*Staphylococcus aureus, Micrococcus roseus*) and Gram-negative bacteria (*Escherichia coli*). The compounds were tested at a concentration of 0.001 mol/ml in DMF against all organisms. The zone of inhibition was compared with the standard drug after 24 h of incubation at 25°C and measured in mm. Results are reported in **Table 1**, and it was found that compounds **2d** and **2e** were highly active against *S. aureus* and *M. roseus*


*Zone of inhibition was expressed in mm.*

*Highly active +++ (inhibition zone >12 mm); moderately active ++ (inhibition zone 9–12 mm); slightly active + (inhibition zone 6–9 mm); and inactive (inhibition zone <6 mm).*

#### **Table 1.**

*Antimicrobial activity tests of dihydroazeto[2*′*,3*′*:4,5]seleno[2,3-*b*]quinolines (2a–e).*

(Gram-positive) and moderately active against *E. coli* (Gram-negative), and compound **2c** was slightly active against *M. roseus* and *E. coli*. Compound **2e** was slightly active against *S. aureus* and *M. roseus*, and compounds **2a** and **2b** were slightly active against *M. roseus.* Other compounds were all inactive against these three pathogenic microorganisms. Hence, further studies in these compounds are planned to obtain clinically useful agents.

### **Author details**

B.P. Nandeshwarappa1 \*, G.K. Prakash<sup>2</sup> and S.O. Sadashiv3

1 Department of PG Studies and Research in Chemistry, Shivagangothri, Davangere University, Davangere, Karnataka, India

2 Department of Chemistry, Bapuji Institute of Engineering and Technology, Davangere, India

3 Department of Food Science and Technology, Shivagangothri, Davangere University, Davangere, Karnataka, India

\*Address all correspondence to: belakatte@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**7**

2006;**15**:153

1996. p. 245

*Introductory Chapter: Synthesis and Antimicrobial Activities of Dihydroazeto[2′,3′:4,5]…*

[8] Mukerjee AK, Singh AK. β-Lactams: retrospect and prospect. Tetrahedron.

[9] Kametani T. Synthesis of carbapenem antibiotics. Heterocycles. 1982;**17**:463

carbapenem antibiotics. Heterocycles.

[11] Laila MG, Fatema DE. Mansoura Journal of Pharmaceutical Sciences/ Chemical Abstrcts. 1996;**125**:114552

[12] Koniya T. LRES Lab, Suiisawa Pharma Co. Ltd, Osaka (Japan) Kugaku No Ryoiki Zokon. Chemical Abstracts.

[13] Maffii G. Lepetit S P A, Milan Italy, Farmaco (Pavia)/Chemical Abstracts.

1946/1977;**29/86**:112/1656a

1954/1959;**14/53**:176/20553B

[14] Shah SK, Peter BL. European Patent Application, Ep 360/Chemical Abstracts. 1986/1989;**110**:173037a

[15] Cooper and Robin David Gray. European Patent Application, Ep 252/Chemical Abstracts. 1988/1989;**744/10**:4934

[16] Firestone RA, Barker PL, Pisano JM, Ashe BM, Dahlgren ME. Monocyclic β-lactam inhibitors of human leukocyte elastase. Tetrahedron. 1990;**46**:2255

[17] Nandeshwarappa BP, Aruna Kumar DB, Bhojya Naik HS, Mahadevan KM. An efficient microwave-assisted synthesis of thieno [2, 3-b] quinolines under solvent-free conditions. Journal of Sulfur Chemistry. 2005;**26**(4-5):373

[18] Nandeshwarappa BP, Aruna Kumar DB, Kumaraswamy MN, Ravi Kumar YS, Naik HSB, Mahadevan KM. Microwave assisted synthesis of some novel thiopyrano[2,3-b]quinolines

[10] Nagahara T, Kametani T. Enantioselective syntheses of

1978;**34**:1731

1987;**25**:729

*DOI: http://dx.doi.org/10.5772/intechopen.92030*

[1] Thomys H. Chemical constituents of the rutaceae. Berichte der Deutschen Pharmazeutischen Gesellschaft.

[2] Nandeshwarappa BP, Arun Kumar DB, Kumaraswamy MN, Ravikumar YS, Bhojya Naik HS, Mahadevan KM. Microwave assisted synthesis of some novel thiopyrano[2,3-b]quinolines as a new class of antimicrobial agent. Phosphorous, Sulfur, and Silicon and the Related Elements. 2006;**181**:1545

[3] Bhojya Naik HS, Ramesha MS, Shwetha BV, Roopa TR. A facile synthesis of novel 9-methyl[1, 2, 3] selenadiazoles[4, 5-b]quinoline and 9-methyl[1, 2, 3]thiadiazole[4, 5-b] quinoline as a new class of antimicrobial agents. Phosphorous, Sulfur, and Silicon and the Related Elements. 2006;**81**:533

[4] Nandeshwarappa BP, Arun Kumar DB, Bhojya Naik HS, Mahadevan KM. An efficient microwave-assisted synthesis of thieno[2,3-b]quinolines under solvent-free conditions. Journal of Sulfur Chemistry. 2005;**26**(4-5):373

[5] Raghavendra M, Bhojya Naik HS, Sherigara BS. Microwave induced synthesis of thieno[2,3-b]quinoline-2-carboxylic acids and alkyl esters and their antibacterial activity. Journal of Sulfur Chemistry. 2006;**27**(4):1

[6] Raghavendra M, Bhojya Naik HS, Sherigara BS. One pot synthesis of some new 2-hydrazino-[1,3,4]thiadiazepino [7,6-b]quinolines under microwave irradiation conditions. Arkivoc.

[7] Michael JP, Natural Products Reports. 1997;**14**:605. b) Balasubramanian M, Keay JG. Comprehensive Heterocyclic Chemistry, II, Vol. 5. In: Katrizky AR, Rees CW, Scriven EFV, editors. Oxford: Pergamon Press, Vol. 06, Chapter 5;

1923;**33**:68

**References**

*Introductory Chapter: Synthesis and Antimicrobial Activities of Dihydroazeto[2′,3′:4,5]… DOI: http://dx.doi.org/10.5772/intechopen.92030*

#### **References**

*Heterocycles - Synthesis and Biological Activities*

**Compound number Microorganisms**

*Antimicrobial activity tests of dihydroazeto[2*′*,3*′*:4,5]seleno[2,3-*b*]quinolines (2a–e).*

\*, G.K. Prakash<sup>2</sup>

clinically useful agents.

**Author details**

Davangere, India

B.P. Nandeshwarappa1

University, Davangere, Karnataka, India

University, Davangere, Karnataka, India

provided the original work is properly cited.

\*Address all correspondence to: belakatte@gmail.com

*Zone of inhibition was expressed in mm.*

*(inhibition zone 6–9 mm); and inactive (inhibition zone <6 mm).*

Ampicillin 2a 2b 2c 2d 2e

**Table 1.**

(Gram-positive) and moderately active against *E. coli* (Gram-negative), and compound **2c** was slightly active against *M. roseus* and *E. coli*. Compound **2e** was slightly active against *S. aureus* and *M. roseus*, and compounds **2a** and **2b** were slightly active against *M. roseus.* Other compounds were all inactive against these three pathogenic microorganisms. Hence, further studies in these compounds are planned to obtain

and S.O. Sadashiv3

1 Department of PG Studies and Research in Chemistry, Shivagangothri, Davangere

2 Department of Chemistry, Bapuji Institute of Engineering and Technology,

3 Department of Food Science and Technology, Shivagangothri, Davangere

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Highly active +++ (inhibition zone >12 mm); moderately active ++ (inhibition zone 9–12 mm); slightly active +* 

*S. aureus M. roseus E. coli*

**6**

[1] Thomys H. Chemical constituents of the rutaceae. Berichte der Deutschen Pharmazeutischen Gesellschaft. 1923;**33**:68

[2] Nandeshwarappa BP, Arun Kumar DB, Kumaraswamy MN, Ravikumar YS, Bhojya Naik HS, Mahadevan KM. Microwave assisted synthesis of some novel thiopyrano[2,3-b]quinolines as a new class of antimicrobial agent. Phosphorous, Sulfur, and Silicon and the Related Elements. 2006;**181**:1545

[3] Bhojya Naik HS, Ramesha MS, Shwetha BV, Roopa TR. A facile synthesis of novel 9-methyl[1, 2, 3] selenadiazoles[4, 5-b]quinoline and 9-methyl[1, 2, 3]thiadiazole[4, 5-b] quinoline as a new class of antimicrobial agents. Phosphorous, Sulfur, and Silicon and the Related Elements. 2006;**81**:533

[4] Nandeshwarappa BP, Arun Kumar DB, Bhojya Naik HS, Mahadevan KM. An efficient microwave-assisted synthesis of thieno[2,3-b]quinolines under solvent-free conditions. Journal of Sulfur Chemistry. 2005;**26**(4-5):373

[5] Raghavendra M, Bhojya Naik HS, Sherigara BS. Microwave induced synthesis of thieno[2,3-b]quinoline-2-carboxylic acids and alkyl esters and their antibacterial activity. Journal of Sulfur Chemistry. 2006;**27**(4):1

[6] Raghavendra M, Bhojya Naik HS, Sherigara BS. One pot synthesis of some new 2-hydrazino-[1,3,4]thiadiazepino [7,6-b]quinolines under microwave irradiation conditions. Arkivoc. 2006;**15**:153

[7] Michael JP, Natural Products Reports. 1997;**14**:605. b) Balasubramanian M, Keay JG. Comprehensive Heterocyclic Chemistry, II, Vol. 5. In: Katrizky AR, Rees CW, Scriven EFV, editors. Oxford: Pergamon Press, Vol. 06, Chapter 5; 1996. p. 245

[8] Mukerjee AK, Singh AK. β-Lactams: retrospect and prospect. Tetrahedron. 1978;**34**:1731

[9] Kametani T. Synthesis of carbapenem antibiotics. Heterocycles. 1982;**17**:463

[10] Nagahara T, Kametani T. Enantioselective syntheses of carbapenem antibiotics. Heterocycles. 1987;**25**:729

[11] Laila MG, Fatema DE. Mansoura Journal of Pharmaceutical Sciences/ Chemical Abstrcts. 1996;**125**:114552

[12] Koniya T. LRES Lab, Suiisawa Pharma Co. Ltd, Osaka (Japan) Kugaku No Ryoiki Zokon. Chemical Abstracts. 1946/1977;**29/86**:112/1656a

[13] Maffii G. Lepetit S P A, Milan Italy, Farmaco (Pavia)/Chemical Abstracts. 1954/1959;**14/53**:176/20553B

[14] Shah SK, Peter BL. European Patent Application, Ep 360/Chemical Abstracts. 1986/1989;**110**:173037a

[15] Cooper and Robin David Gray. European Patent Application, Ep 252/Chemical Abstracts. 1988/1989;**744/10**:4934

[16] Firestone RA, Barker PL, Pisano JM, Ashe BM, Dahlgren ME. Monocyclic β-lactam inhibitors of human leukocyte elastase. Tetrahedron. 1990;**46**:2255

[17] Nandeshwarappa BP, Aruna Kumar DB, Bhojya Naik HS, Mahadevan KM. An efficient microwave-assisted synthesis of thieno [2, 3-b] quinolines under solvent-free conditions. Journal of Sulfur Chemistry. 2005;**26**(4-5):373

[18] Nandeshwarappa BP, Aruna Kumar DB, Kumaraswamy MN, Ravi Kumar YS, Naik HSB, Mahadevan KM. Microwave assisted synthesis of some novel thiopyrano[2,3-b]quinolines

as a new class of antimicrobial agent. Phosphorus, Sulfur, and Silicon and the Related Elements. 2006;**81**:1545

[19] Nandeshwarappa BP, Aruna Kumar DB, Bhojya Naik HS, Mahadevan KM. A fast and largescale synthesis of 3-formyl-2 mercaptoquinolines. Phosphorus, Sulfur, and Silicon and the Related Elements. 2006;**181**:1997

[20] Kiran BM, Nandeshwarappa BP, Vaidya VP, Mahadevan KM. Chemistry of substituted quinolines: thieno [2, 3-b] and thiopyrano [2, 3-b] quinolines. Phosphorus, Sulfur, and Silicon and the Related Elements. 2007;**182**:969

[21] Kiran BM, Nandeshwarappa BP, Prakash GK, Vaidya VP, Mahadevan K. Synthesis of new seleno-substituted quinolines. Phosphorus, Sulfur, and Silicon and the Related Elements. 2007;**182**:993

[22] Nandeshwarappa BP. Solvent free, inorganic solid supported synthesis of furoquinolines under microwave irradiation: A potent antimicrobial agent. Journal of Chemistry and Chemical Sciences. 2017;**7**(1):15

[23] Nandeshwarappa BP, Manjunatha Swamy HM. New and efficient synthesis of [(3-formylquinolin-2-yl)thio] acetic acids. Journal of Chemistry and Chemical Sciences. 2017;**7**(2):131

[24] Nandeshwarappa BP. Novel synthesis of new thieno [2,3-b] quinoline-2-carboxylates. Journal of Chemistry and Chemical Sciences. 2017;**7**(3):230

[25] Nandeshwarappa BP. A facile synthesis of sulfur containing condensed quinolines. Journal of Chemistry and Chemical Sciences. 2017;**7**(3):222

[26] Nandeshwarappa BP. Novel approach towards synthesis of ethyl [(3-formylquinolin-2-yl)thio]acetate. Journal of Chemistry and Chemical Sciences. 2017;**7**(3):237

[27] Nandeshwarappa BP. An efficient synthesis of ethyl {[3-(hydroxymethyl) quinolin-2-yl]thio}acetate. Journal of Chemistry and Chemical Sciences. 2017;**7**(3):242

[28] Nandeshwarappa BP. Synthesis of {[3-(hydroxymethyl)quinolin-2-yl] thio} acetic acid. Journal of Chemistry and Chemical Sciences. 2017;**7**(3):247

[29] Nandeshwarappa BP. Synthesis of ethyl {[3-(chloromethyl)quinolin-2-yl] sulfanyl}acetate. Journal of Chemistry and Chemical Sciences. 2017;**7**(3):256

[30] Nandeshwarappa BP. Rapid synthesis of 5H-[1,4]oxathiepino[5,6-b] quinolin-3(2H)-ones. Journal of Chemistry and Chemical Sciences. 2017;**7**(3):251

[31] Meth-Kohn O, Narin B, Tarnowski B, Hayes R, Keyzad A, Rhousati S, et al. A versatile new synthesis of quinolines and related fused pyridines. Part 9. Synthetic application of the 2-chloroquinoline-3-carbaldehydes. Journal of the Chemical Society, Perkin Transactions. 1981;**1**:2509

[32] Nandeshwarappa BP, Manjappa S, Kishore B. A novel approach toward the synthesis of azetidinones derivatives. Journal of Sulfur Chemistry. 2011;**32**(5):475

[33] Finegold SM, Martin WJ. Diagnostic Microbiology. 6th ed. London: Mosby; 1982. p. 450

**9**

**Chapter 2**

**Abstract**

and spectral (FTIR, <sup>1</sup>

**1.1 Introduction**

Heterocycles

Phenacyl Bromide: An Organic

Five- and Six-Membered Bioactive

An environmentally friendly, economic synthetic protocol was advanced for synthesis of biologically and pharmacologically vital five- and six-membered heterocycles containing nitrogen, sulphur and oxygen as heteroatom. A series of thiazole derivatives was prepared by the reaction of substituted phenacyl halides and phenyl thiourea in the presence of TiO2 nanoparticles (NPs) as nanocatalyst in DCM. Similarly, another series of six-membered heterocyclic compounds were synthesized by the reaction of phenacyl halides with phenylenediamine, 2-aminophenol, 2-aminobenzenethiol to produce corresponding products (1,4-quinoxaline, benzoxazine, benzothiazine) under catalytic effect of TiO2nanocatalyst. Analytical

H and 13C NMR and SEM) techniques were employed for the

Intermediate for Synthesis of

*Dinesh Kumar Jangid and Surbhi Dhadda*

structural elucidation of the synthesized compounds.

1,4-quinoxaline, benzoxazine, benzothiazine

This chapter is divided into two sections:

**Keywords:** environmentally friendly, thiazole derivatives, nanocatalyst,

1.Synthesis of five-membered heterocylces from phenacyl halides

2.Synthesis of six-membered heterocylces from phenacyl halides

**1. Synthesis of five-membered heterocylces from phenacyl halides**

Cyclic compounds which contain one or more hetero atoms besides carbon are called heterocyclic compounds. Most commonly nitrogen, sulphur and oxygen are present as hetero atoms. Phosphorous, tin, boron, silicon, etc. are other less common hetero atoms. Numerous heterocyclic compounds have three to six atoms in the ring, but only those compounds which have five- or six-membered ring are by far most significant. Heterocyclic compounds are broadly circulated in nature and are

### **Chapter 2**

## Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive Heterocycles

*Dinesh Kumar Jangid and Surbhi Dhadda*

### **Abstract**

An environmentally friendly, economic synthetic protocol was advanced for synthesis of biologically and pharmacologically vital five- and six-membered heterocycles containing nitrogen, sulphur and oxygen as heteroatom. A series of thiazole derivatives was prepared by the reaction of substituted phenacyl halides and phenyl thiourea in the presence of TiO2 nanoparticles (NPs) as nanocatalyst in DCM. Similarly, another series of six-membered heterocyclic compounds were synthesized by the reaction of phenacyl halides with phenylenediamine, 2-aminophenol, 2-aminobenzenethiol to produce corresponding products (1,4-quinoxaline, benzoxazine, benzothiazine) under catalytic effect of TiO2nanocatalyst. Analytical and spectral (FTIR, <sup>1</sup> H and 13C NMR and SEM) techniques were employed for the structural elucidation of the synthesized compounds.

**Keywords:** environmentally friendly, thiazole derivatives, nanocatalyst, 1,4-quinoxaline, benzoxazine, benzothiazine

This chapter is divided into two sections:


#### **1. Synthesis of five-membered heterocylces from phenacyl halides**

#### **1.1 Introduction**

Cyclic compounds which contain one or more hetero atoms besides carbon are called heterocyclic compounds. Most commonly nitrogen, sulphur and oxygen are present as hetero atoms. Phosphorous, tin, boron, silicon, etc. are other less common hetero atoms. Numerous heterocyclic compounds have three to six atoms in the ring, but only those compounds which have five- or six-membered ring are by far most significant. Heterocyclic compounds are broadly circulated in nature and are

**8**

*Heterocycles - Synthesis and Biological Activities*

as a new class of antimicrobial agent. Phosphorus, Sulfur, and Silicon and the [(3-formylquinolin-2-yl)thio]acetate. Journal of Chemistry and Chemical

[27] Nandeshwarappa BP. An efficient synthesis of ethyl {[3-(hydroxymethyl) quinolin-2-yl]thio}acetate. Journal of Chemistry and Chemical Sciences.

[28] Nandeshwarappa BP. Synthesis of {[3-(hydroxymethyl)quinolin-2-yl] thio} acetic acid. Journal of Chemistry and Chemical Sciences. 2017;**7**(3):247

[29] Nandeshwarappa BP. Synthesis of ethyl {[3-(chloromethyl)quinolin-2-yl] sulfanyl}acetate. Journal of Chemistry and Chemical Sciences. 2017;**7**(3):256

synthesis of 5H-[1,4]oxathiepino[5,6-b] quinolin-3(2H)-ones. Journal of Chemistry and Chemical Sciences.

[31] Meth-Kohn O, Narin B, Tarnowski B, Hayes R, Keyzad A, Rhousati S, et al. A versatile new synthesis of quinolines and related fused pyridines. Part 9. Synthetic application of the 2-chloroquinoline-3-carbaldehydes. Journal of the Chemical Society, Perkin

[32] Nandeshwarappa BP, Manjappa S, Kishore B. A novel approach toward the synthesis of azetidinones

derivatives. Journal of Sulfur Chemistry.

[33] Finegold SM, Martin WJ. Diagnostic Microbiology. 6th ed. London: Mosby;

[30] Nandeshwarappa BP. Rapid

Transactions. 1981;**1**:2509

2011;**32**(5):475

1982. p. 450

Sciences. 2017;**7**(3):237

2017;**7**(3):242

2017;**7**(3):251

Related Elements. 2006;**81**:1545

[19] Nandeshwarappa BP, Aruna Kumar DB, Bhojya Naik HS, Mahadevan KM. A fast and largescale synthesis of 3-formyl-2 mercaptoquinolines. Phosphorus, Sulfur, and Silicon and the Related

[20] Kiran BM, Nandeshwarappa BP, Vaidya VP, Mahadevan KM. Chemistry of substituted quinolines: thieno [2, 3-b] and thiopyrano [2, 3-b] quinolines. Phosphorus, Sulfur, and Silicon and the

Related Elements. 2007;**182**:969

2007;**182**:993

2017;**7**(3):230

2017;**7**(3):222

[21] Kiran BM, Nandeshwarappa BP, Prakash GK, Vaidya VP, Mahadevan K. Synthesis of new seleno-substituted quinolines. Phosphorus, Sulfur, and Silicon and the Related Elements.

[22] Nandeshwarappa BP. Solvent free, inorganic solid supported synthesis of furoquinolines under microwave irradiation: A potent antimicrobial agent. Journal of Chemistry and Chemical Sciences. 2017;**7**(1):15

[23] Nandeshwarappa BP, Manjunatha Swamy HM. New and efficient synthesis

of [(3-formylquinolin-2-yl)thio] acetic acids. Journal of Chemistry and Chemical Sciences. 2017;**7**(2):131

[24] Nandeshwarappa BP. Novel synthesis of new thieno [2,3-b] quinoline-2-carboxylates. Journal of Chemistry and Chemical Sciences.

[25] Nandeshwarappa BP. A facile synthesis of sulfur containing condensed quinolines. Journal of Chemistry and Chemical Sciences.

[26] Nandeshwarappa BP. Novel approach towards synthesis of ethyl

Elements. 2006;**181**:1997

predominantly important because of the extensive variety of physiological activities related with this course of substances. Several of the important compounds contain heterocyclic rings, e.g. most of the members of alkaloids, vitamin B complex, chlorophyll, antibiotics, other plants pigments, dyes, amino acids, enzymes, the genetic material, DNA, drugs, etc. These biologically active molecules always drawn the attention of chemist over the years specifically because of their biological significance.

One striking structural article characteristic to heterocycles, which continue to be exploited to great benefit by the drug industry, lies in their capability to manifest substituents around a core scaffolds in sharp three-dimensional representations [1]. In early studies of chemistry, nitrogen and sulphur containing heterocyclic compounds contained predominantly and they were thoroughly associated with the enlargement of organic chemistry which was concerned with the study of materials separated from living sources and are widely used as structural motif in drug discovery [2].

Heterocycles form by far the leading classical splits of organic chemistry and are of enormous prominence in the biological and industrial field. One of the major causes for the extensive use of heterocyclic compounds is their structures that can be precisely manipulated to attain the required alteration in function. Another important feature embraced by heterocycles is the possibility of incorporating functional groups either as substituents or as the part of ring system itself. They are also the integral part of the wide range of drugs, most of the vitamins, biomolecules, many natural products, and biologically active compounds, including antifungal, antitumor, antimicrobial [3], antibiotic, anti-inflammatory, antidepressant, antimalarial [4] antibacterial, antiviral, herbicidal, anti-HIV, antidiabetic, insecticidal and fungicidal agents. Further, most of the heterocycles possess vital applications in materials science such as dyestuff, fluorescent sensor, plastics, information storage, brightening agents, and analytical reagents. In addition, they have applications in polymer and supramolecular chemistry, especially in conjugated polymers. Moreover, they act as organic light-emitting diodes (OLEDs), organic conductors, light harvesting systems, photovoltaic cells, optical data carriers [5], chemically controllable switches, semiconductors, molecular wires, and liquid crystalline compounds. Thus consideration has been given to advanced effective new methods to synthesize heterocycles.

Now, nanotechnologies are broadly considered to have the potential to bring assistances in area as diverse as water contamination, drug development, information and communication technologies and the production of lighter and strong materials. Nanotechnologies include the conception and manipulation of materials at the nanometre scale, either by refining or reducing bulk materials or by scaling up from single groups of atoms. Nanoparticles (1–100 nm size) have a distinctive place in nanoscience and nanotechnology, not only because of their specific properties subsequent from their reduced dimensions, but also because they are auspicious building blocks for more complex nanostructures. Nanoparticles with the diameter of less than 10 nm have created extreme curiosity over the past decade due to their developed potential application in area such as nanoscale electronics, sensors, optics and catalysis. Due to this importance of nanoparticles so many efforts have been devoted to the synthesis of nanoparticles from last few years.

Furthermore, the *α*-halogenation of ketones is an important conversion in synthetic organic chemistry [6]. Due to high reactivity of *α*-bromoketones, they react with a large number of nucleophiles which provide a range of biologically active compounds [7]. *α*-bromoacetophenone derivatives have been examined for their active contribution in the inhibition of protein tyrosine phosphatase such as PTP1B and SHP-1 [8]. Bromination of 1,3-keto compounds at the reactive position increases bioactivity, mainly cytotoxicity against breast cancer 1A9 cells, with respect to the unsubstituted compound [9].

**11**

*Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive…*

For several conversions employed in organic and pharmaceutical synthesis, especially, *α*-bromo carbonyl compounds have become a significant structural motif for the development of numerous biologically active compounds for instancethiazolidin-4-one, quinoxalines [10], cyclohexanone derivatives, thiophene, pyrazolo[1,5-*α*][1,3,5]triazine, imidazo[1,2-a][1,3,5]triazin, pyrazolines, imidazo[2,1-b] benzothiazoles [11], thiadiazine and triazolo[3,4-b][1,3,4]thiadiazine. Additionally, they are adaptable building blocks for the retro-synthesis of natural products. *α*-bromoalkanones were prepared by direct method from *α*-bromination of carbonyl compounds, which has fascinated significant consideration in the synthetic organic chemistry [12]. The brominated products are important intermediates for the synthesis of various useful molecules such as pharmaceuticals, surfactants, pesticides and biologically active heterocyclic compounds [13]. *α*-Bromination is also a crucial step for introducing a functional group into a molecule for further conversions. *α*-Halogenated carbonyl compounds are broadly used in organic synthesis as appreciated reaction intermediates and they

Thiazole ring containing heterocyclic systems are a significant structural entity

Previously many synthetic methods have been used to synthesize *α*-halo carbonyl compounds and various reagents have been applied for halogenation of active *α*-hydrogen of carbonyl compounds such as bromine has been previously used as a elementary brominating reagent for the *α*-bromination of carbonyl compounds but bromine is very harmful chemical to use. To overcome this limitation, several different reagents such as copper(II) bromide [17], tribromoacetophenone [18], 1,4-dioxane bromooxonium bromide [19], pyridium and tetrabutylammonium tribromide have also been employed as substitutions to bromine. The most commonly used reagents for a-bromination of ketones include molecular bromine [20], N-bromosuccinimide (NBS) [21]. Recently, various methods have been reported using NBS-NH4OAc [22], NBS-photochemical [23], NBS-PTSA [24], NBS-silica supported sodium hydrogen sulphate [25], NBS-Amberlyst-15 [26], NBS-Lewis acids [27], NBS-ionic liquids [28], MgBr2-(hydroxy(tosyloxy)iodo)benzene-MW [29], N-methylpyrrolidin-2-one hydrotribromide (MPHT) [30], (CH3)3SiBr-KNO3

Here we are reporting a new efficient synthetic procedure for the synthesis of *α*-halo acetophenoes and thiazole derivatives using heterogeneous catalyst TiO2 NPs. Presented route is more advanced, eco-friendly and more efficient.

All the required chemicals were purchased from Sigma Aldrich, Alpha Aesar and used without further purification. The melting points were checked in open capillary tubes in melting point apparatus and are uncorrected. The completion of the reaction was checked on TLC plates coated with silica gel-G in the

for several bioactive molecules [14]. Thiazole has been used in the preparation of imperative drugs essential for antibacterial treatment, inflammation and possesses immunosuppressant activity [15]. It also possesses inhibitor's activity against antiallergies, enzyme cyclo-independent kinase, antitumor and schizophrenia [16]. Some of the thiazole derivatives prepared as fungicide as well as preventing in vivo growth of *Xanthomonas* and anti-arthritis. Amino-thiazoles act as an oestrogen receptor and as a potent class of adenosine receptor antagonists. Development of heterocyclic chemistry is still in advance phase where lot of scope is accessible for researcher. In continuation of this research, various publications on development of biologically active heterocycles containing nitrogen and sulfur as heteroatom in

*DOI: http://dx.doi.org/10.5772/intechopen.88243*

show versatile uses in organic conversions.

recent years have come into light.

[31], BDMS, NaBr [32].

**1.2 Experimental details**

#### *Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive… DOI: http://dx.doi.org/10.5772/intechopen.88243*

For several conversions employed in organic and pharmaceutical synthesis, especially, *α*-bromo carbonyl compounds have become a significant structural motif for the development of numerous biologically active compounds for instancethiazolidin-4-one, quinoxalines [10], cyclohexanone derivatives, thiophene, pyrazolo[1,5-*α*][1,3,5]triazine, imidazo[1,2-a][1,3,5]triazin, pyrazolines, imidazo[2,1-b] benzothiazoles [11], thiadiazine and triazolo[3,4-b][1,3,4]thiadiazine. Additionally, they are adaptable building blocks for the retro-synthesis of natural products. *α*-bromoalkanones were prepared by direct method from *α*-bromination of carbonyl compounds, which has fascinated significant consideration in the synthetic organic chemistry [12]. The brominated products are important intermediates for the synthesis of various useful molecules such as pharmaceuticals, surfactants, pesticides and biologically active heterocyclic compounds [13]. *α*-Bromination is also a crucial step for introducing a functional group into a molecule for further conversions. *α*-Halogenated carbonyl compounds are broadly used in organic synthesis as appreciated reaction intermediates and they show versatile uses in organic conversions.

Thiazole ring containing heterocyclic systems are a significant structural entity for several bioactive molecules [14]. Thiazole has been used in the preparation of imperative drugs essential for antibacterial treatment, inflammation and possesses immunosuppressant activity [15]. It also possesses inhibitor's activity against antiallergies, enzyme cyclo-independent kinase, antitumor and schizophrenia [16]. Some of the thiazole derivatives prepared as fungicide as well as preventing in vivo growth of *Xanthomonas* and anti-arthritis. Amino-thiazoles act as an oestrogen receptor and as a potent class of adenosine receptor antagonists. Development of heterocyclic chemistry is still in advance phase where lot of scope is accessible for researcher. In continuation of this research, various publications on development of biologically active heterocycles containing nitrogen and sulfur as heteroatom in recent years have come into light.

Previously many synthetic methods have been used to synthesize *α*-halo carbonyl compounds and various reagents have been applied for halogenation of active *α*-hydrogen of carbonyl compounds such as bromine has been previously used as a elementary brominating reagent for the *α*-bromination of carbonyl compounds but bromine is very harmful chemical to use. To overcome this limitation, several different reagents such as copper(II) bromide [17], tribromoacetophenone [18], 1,4-dioxane bromooxonium bromide [19], pyridium and tetrabutylammonium tribromide have also been employed as substitutions to bromine. The most commonly used reagents for a-bromination of ketones include molecular bromine [20], N-bromosuccinimide (NBS) [21]. Recently, various methods have been reported using NBS-NH4OAc [22], NBS-photochemical [23], NBS-PTSA [24], NBS-silica supported sodium hydrogen sulphate [25], NBS-Amberlyst-15 [26], NBS-Lewis acids [27], NBS-ionic liquids [28], MgBr2-(hydroxy(tosyloxy)iodo)benzene-MW [29], N-methylpyrrolidin-2-one hydrotribromide (MPHT) [30], (CH3)3SiBr-KNO3 [31], BDMS, NaBr [32].

Here we are reporting a new efficient synthetic procedure for the synthesis of *α*-halo acetophenoes and thiazole derivatives using heterogeneous catalyst TiO2 NPs. Presented route is more advanced, eco-friendly and more efficient.

#### **1.2 Experimental details**

All the required chemicals were purchased from Sigma Aldrich, Alpha Aesar and used without further purification. The melting points were checked in open capillary tubes in melting point apparatus and are uncorrected. The completion of the reaction was checked on TLC plates coated with silica gel-G in the

*Heterocycles - Synthesis and Biological Activities*

significance.

predominantly important because of the extensive variety of physiological activities related with this course of substances. Several of the important compounds contain heterocyclic rings, e.g. most of the members of alkaloids, vitamin B complex, chlorophyll, antibiotics, other plants pigments, dyes, amino acids, enzymes, the genetic material, DNA, drugs, etc. These biologically active molecules always drawn the attention of chemist over the years specifically because of their biological

One striking structural article characteristic to heterocycles, which continue to be exploited to great benefit by the drug industry, lies in their capability to manifest substituents around a core scaffolds in sharp three-dimensional representations [1]. In early studies of chemistry, nitrogen and sulphur containing heterocyclic compounds contained predominantly and they were thoroughly associated with the enlargement of organic chemistry which was concerned with the study of materials separated from living sources and are widely used as structural motif in drug discovery [2]. Heterocycles form by far the leading classical splits of organic chemistry and are of enormous prominence in the biological and industrial field. One of the major causes for the extensive use of heterocyclic compounds is their structures that can be precisely manipulated to attain the required alteration in function. Another important feature embraced by heterocycles is the possibility of incorporating functional groups either as substituents or as the part of ring system itself. They are also the integral part of the wide range of drugs, most of the vitamins, biomolecules, many natural products, and biologically active compounds, including antifungal, antitumor, antimicrobial [3], antibiotic, anti-inflammatory, antidepressant, antimalarial [4] antibacterial, antiviral, herbicidal, anti-HIV, antidiabetic, insecticidal and fungicidal agents. Further, most of the heterocycles possess vital applications in materials science such as dyestuff, fluorescent sensor, plastics, information storage, brightening agents, and analytical reagents. In addition, they have applications in polymer and supramolecular chemistry, especially in conjugated polymers. Moreover, they act as organic light-emitting diodes (OLEDs), organic conductors, light harvesting systems, photovoltaic cells, optical data carriers [5], chemically controllable switches, semiconductors, molecular wires, and liquid crystalline compounds. Thus consideration has been given to advanced effective new methods to synthesize heterocycles. Now, nanotechnologies are broadly considered to have the potential to bring assistances in area as diverse as water contamination, drug development, information and communication technologies and the production of lighter and strong materials. Nanotechnologies include the conception and manipulation of materials at the nanometre scale, either by refining or reducing bulk materials or by scaling up from single groups of atoms. Nanoparticles (1–100 nm size) have a distinctive place in nanoscience and nanotechnology, not only because of their specific properties subsequent from their reduced dimensions, but also because they are auspicious building blocks for more complex nanostructures. Nanoparticles with the diameter of less than 10 nm have created extreme curiosity over the past decade due to their developed potential application in area such as nanoscale electronics, sensors, optics and catalysis. Due to this importance of nanoparticles so many efforts have

been devoted to the synthesis of nanoparticles from last few years.

respect to the unsubstituted compound [9].

Furthermore, the *α*-halogenation of ketones is an important conversion in synthetic organic chemistry [6]. Due to high reactivity of *α*-bromoketones, they react with a large number of nucleophiles which provide a range of biologically active compounds [7]. *α*-bromoacetophenone derivatives have been examined for their active contribution in the inhibition of protein tyrosine phosphatase such as PTP1B and SHP-1 [8]. Bromination of 1,3-keto compounds at the reactive position increases bioactivity, mainly cytotoxicity against breast cancer 1A9 cells, with

**10**

n-hexane-EtOAc (v/v = 7:3) and visualised by exposure in UV chamber. The IR spectra were recorded on Shimadzu IR-435 spectrophotometer (νmax in cm<sup>−</sup><sup>1</sup> ). 1 H NMR, and 13C NMR spectra were recorded using a JEOL RESONANCE Spectrometer at 400.0 and 100.0 MHz respectively (δ in ppm) using TMS (d = 0.0) as an internal standard for <sup>1</sup> H NMR, and CDCl3 was used as internal standard (d = 77.0) for 13C NMR. Chemical shifts are reported in parts per million (ppm) as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad). The elemental analysis (C, H and N) were performed using vario-III analyser. The nanoparticles are characterized by FTIR and SEM.

#### *1.2.1 General procedure for the synthesis of TiO2 NPs*

TiO2 NPs were prepared by sol-gel method [33], using titanium(IV) isopropoxide. For the synthesis of TiO2 NPs, [Ti{OPr<sup>i</sup> }4] (1.75 g) was taken in round bottom flask with dry isopropanol (~35 ml). 2–3 drops of water-isopropanol mixture (1,1) was added to the above mentioned clear solution and magnetically stirred for 2 h then sol formation occurred immediately. To ensure complete hydrolysis, excess of water ~10 ml {stoichiometric amount (0.22 g)}, in small lots with continuous stirring for ~4 h was added. The mixture was again stirred for 1 h, till a gel is formed. The synthesized gel was dried in an oven (100°C) and then washed properly with acetone then an off-white powder was obtained. This powder was sintered at 600°C for 4 h to yield a white powder, which was characterized by FTIR and SEM as pure TiO2.

#### *1.2.2 Characterization of TiO2 NPs*

The TiO2 nanocatalyst was prepared using sol-gel method and characterized by various techniques using FT-IR and Scanning Electron Microscopy (SEM). The FT-IR spectrum of TiO2 NPs is given in **Figure 1**. The absorbance bands at around 3235–3550 cm<sup>−</sup><sup>1</sup> were proved to the adsorbed water and hydroxyl group in nano sized TiO2 (**Figure 1**). The band observed at 720 cm<sup>−</sup><sup>1</sup> is due to Ti-O-Ti while absorbance bands at 460 cm<sup>−</sup><sup>1</sup> show stretching vibration due to Ti-O, which is customary with the reported IR spectra for nano TiO2 [33]. The SEM images of this oxide are revealed in **Figure 2**. The scales that are shown in **Figure 2** are of 500 nm come into sight to specify formation of agglomerates granular morphology, constituted by nano-sized crystallites.

**13**

*Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive…*

*1.2.3 General procedure for the synthesis of substituted thiazoles (***3a–e***)*

*1.3.1 [4-(4-Bromo-phenyl)-thiazole-2-yl]-(4-chloro-phenyl)-amine (***3a***)*

, KBr): 3315, 1611, 1462, 1370, 762, 644; 1

*1.3.2 [4-(4-Chloro-phenyl)-thiazole-2-yl]-phenyl-amine (***3b***)*

131.9, 132.3, 140.6, 150.3, 176.9; HRMS; *m*/*z* 286.03 (M+

62.82; H, 3.87; N, 9.77; found C, 62.83; H, 3.89; N, 9.78.

*1.3.3 [4-(4-Methoxy-phenyl)-thiazole-2-yl]-phenyl-amine (***3c***)*

131.8, 131.9, 132.4, 140.6, 150.7, 177.5; HRMS; *m*/*z* 282.08 (M<sup>+</sup>

calcd. C, 68.06; H, 5.00; N, 9.92; found C, 68.08; H, 5.02; N, 9.93.

, KBr): 3317, 1633, 1467, 1379, 767, 648; <sup>1</sup>

δ 4.07 (s, NH), 7.18 (d, 2H, Ar–H), 7.39 (d, 2H, Ar–H), 7.48 (d, 2H, Ar–H), 7.56(d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 109.5, 112.5, 120.6, 130.7,

, KBr): 3349, 1646, 1434, 1389, 779, 667; 1

was allowed to stir at magnetic stirrer at 50°

*(a and b). The SEM image of the TiO2 NPs.*

synthesis is shown in **Figure 4** (**Table 1**).

IR (cm<sup>−</sup><sup>1</sup>

**Figure 2.**

IR (cm<sup>−</sup><sup>1</sup>

IR (cm<sup>−</sup><sup>1</sup>

**1.3 Spectral data of substituted thiazole (3a–e)**

131.3, 138.6, 149.4, 175.3; HRMS; *m*/*z* 365.94 (M<sup>+</sup>

H, 2.76; N, 7.66; found C, 49.25; H, 2.75; N, 7.69.

In a 20 ml round bottom flask phenacyl bromide (**1**) (0.5 mmol) and substituted phenyl thioureas (**2**) (0.5 mmol) were added in 5 mL DCM. A catalytic amount of TiO2 NPs (5 mol%) is added to reaction mixture. Thereafter, the reaction mixture

tion was monitored by TLC, the solid separated was filtered, washed with Hypo solution and recrystallized with ethanol (**Figure 3**) The detailed mechanism of the

δ 4.03 (s, NH), 7.17 (d, 2H, Ar–H), 7.34 (d, 2H, Ar–H), 7.42 (d, 2H, Ar–H), 7.55 (d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 106.2, 118.5, 119.5, 128.4, 130.5, 131.0,

δ 4.12 (s, NH), 7.18 (d, 2H, Ar–H), 7.42 (d, 2H, Ar–H), 7.45 (d, 2H, Ar–H), 7.57 (d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 107.3, 119.3, 120.7, 130.3, 131.5,

C for 20–30 min. The progress of reac-

H NMR (CDCl3, 400 MHz):

H NMR (CDCl3, 400 MHz):

); C15H11ClN2S: calcd. C,

H NMR (CDCl3, 400 MHz):

); C16H14N2OS:

); C15H10BrClN2S: calcd. C, 49.27;

*DOI: http://dx.doi.org/10.5772/intechopen.88243*

**Figure 1.** *The FT-IR spectra of TiO2 NPs.*

*Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive… DOI: http://dx.doi.org/10.5772/intechopen.88243*

**Figure 2.** *(a and b). The SEM image of the TiO2 NPs.*

*Heterocycles - Synthesis and Biological Activities*

(d = 0.0) as an internal standard for <sup>1</sup>

*1.2.1 General procedure for the synthesis of TiO2 NPs*

sized TiO2 (**Figure 1**). The band observed at 720 cm<sup>−</sup><sup>1</sup>

ide. For the synthesis of TiO2 NPs, [Ti{OPr<sup>i</sup>

*1.2.2 Characterization of TiO2 NPs*

terized by FTIR and SEM.

1

TiO2.

3235–3550 cm<sup>−</sup><sup>1</sup>

bance bands at 460 cm<sup>−</sup><sup>1</sup>

nano-sized crystallites.

n-hexane-EtOAc (v/v = 7:3) and visualised by exposure in UV chamber. The IR spectra were recorded on Shimadzu IR-435 spectrophotometer (νmax in cm<sup>−</sup><sup>1</sup>

H NMR, and CDCl3 was used as internal

}4] (1.75 g) was taken in round bottom

is due to Ti-O-Ti while absor-

H NMR, and 13C NMR spectra were recorded using a JEOL RESONANCE Spectrometer at 400.0 and 100.0 MHz respectively (δ in ppm) using TMS

standard (d = 77.0) for 13C NMR. Chemical shifts are reported in parts per million (ppm) as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad). The elemental analysis (C, H and N) were performed using vario-III analyser. The nanoparticles are charac-

TiO2 NPs were prepared by sol-gel method [33], using titanium(IV) isopropox-

flask with dry isopropanol (~35 ml). 2–3 drops of water-isopropanol mixture (1,1) was added to the above mentioned clear solution and magnetically stirred for 2 h then sol formation occurred immediately. To ensure complete hydrolysis, excess of water ~10 ml {stoichiometric amount (0.22 g)}, in small lots with continuous stirring for ~4 h was added. The mixture was again stirred for 1 h, till a gel is formed. The synthesized gel was dried in an oven (100°C) and then washed properly with acetone then an off-white powder was obtained. This powder was sintered at 600°C for 4 h to yield a white powder, which was characterized by FTIR and SEM as pure

The TiO2 nanocatalyst was prepared using sol-gel method and characterized by various techniques using FT-IR and Scanning Electron Microscopy (SEM). The FT-IR spectrum of TiO2 NPs is given in **Figure 1**. The absorbance bands at around

with the reported IR spectra for nano TiO2 [33]. The SEM images of this oxide are revealed in **Figure 2**. The scales that are shown in **Figure 2** are of 500 nm come into sight to specify formation of agglomerates granular morphology, constituted by

were proved to the adsorbed water and hydroxyl group in nano

show stretching vibration due to Ti-O, which is customary

).

**12**

**Figure 1.**

*The FT-IR spectra of TiO2 NPs.*

#### *1.2.3 General procedure for the synthesis of substituted thiazoles (***3a–e***)*

In a 20 ml round bottom flask phenacyl bromide (**1**) (0.5 mmol) and substituted phenyl thioureas (**2**) (0.5 mmol) were added in 5 mL DCM. A catalytic amount of TiO2 NPs (5 mol%) is added to reaction mixture. Thereafter, the reaction mixture was allowed to stir at magnetic stirrer at 50° C for 20–30 min. The progress of reaction was monitored by TLC, the solid separated was filtered, washed with Hypo solution and recrystallized with ethanol (**Figure 3**) The detailed mechanism of the synthesis is shown in **Figure 4** (**Table 1**).

#### **1.3 Spectral data of substituted thiazole (3a–e)**

#### *1.3.1 [4-(4-Bromo-phenyl)-thiazole-2-yl]-(4-chloro-phenyl)-amine (***3a***)*

IR (cm<sup>−</sup><sup>1</sup> , KBr): 3315, 1611, 1462, 1370, 762, 644; 1 H NMR (CDCl3, 400 MHz): δ 4.03 (s, NH), 7.17 (d, 2H, Ar–H), 7.34 (d, 2H, Ar–H), 7.42 (d, 2H, Ar–H), 7.55 (d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 106.2, 118.5, 119.5, 128.4, 130.5, 131.0, 131.3, 138.6, 149.4, 175.3; HRMS; *m*/*z* 365.94 (M<sup>+</sup> ); C15H10BrClN2S: calcd. C, 49.27; H, 2.76; N, 7.66; found C, 49.25; H, 2.75; N, 7.69.

#### *1.3.2 [4-(4-Chloro-phenyl)-thiazole-2-yl]-phenyl-amine (***3b***)*

IR (cm<sup>−</sup><sup>1</sup> , KBr): 3349, 1646, 1434, 1389, 779, 667; 1 H NMR (CDCl3, 400 MHz): δ 4.12 (s, NH), 7.18 (d, 2H, Ar–H), 7.42 (d, 2H, Ar–H), 7.45 (d, 2H, Ar–H), 7.57 (d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 107.3, 119.3, 120.7, 130.3, 131.5, 131.9, 132.3, 140.6, 150.3, 176.9; HRMS; *m*/*z* 286.03 (M+ ); C15H11ClN2S: calcd. C, 62.82; H, 3.87; N, 9.77; found C, 62.83; H, 3.89; N, 9.78.

#### *1.3.3 [4-(4-Methoxy-phenyl)-thiazole-2-yl]-phenyl-amine (***3c***)*

IR (cm<sup>−</sup><sup>1</sup> , KBr): 3317, 1633, 1467, 1379, 767, 648; <sup>1</sup> H NMR (CDCl3, 400 MHz): δ 4.07 (s, NH), 7.18 (d, 2H, Ar–H), 7.39 (d, 2H, Ar–H), 7.48 (d, 2H, Ar–H), 7.56(d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 109.5, 112.5, 120.6, 130.7, 131.8, 131.9, 132.4, 140.6, 150.7, 177.5; HRMS; *m*/*z* 282.08 (M<sup>+</sup> ); C16H14N2OS: calcd. C, 68.06; H, 5.00; N, 9.92; found C, 68.08; H, 5.02; N, 9.93.

*1.3.4 [4-(4-Fluoro-phenyl)-thiazole-2-yl]-phenyl-amine (***3d***)*

IR (cm<sup>−</sup><sup>1</sup> , KBr): 3340, 1623, 1470, 1389, 766, 665; <sup>1</sup> H NMR (CDCl3, 400 MHz): δ 4.09 (s, NH), 7.21 (d, 2H, Ar–H), 7.37 (d, 2H, Ar–H), 7.45 (d, 2H, Ar–H), 7.58(d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 109.8, 121.7, 123.8, 130.6, 131.6, 131.9, 132.1, 139.7, 151.5, 179.8; HRMS; *m*/*z* 270.06 (M<sup>+</sup> ); C15H11FN2S: calcd. C, 66.65; H, 4.10; N, 10.36; found C, 66.67; H, 4.11; N, 10.37.

#### *1.3.5 [4-(2-Chloro-phenyl)-thiazole-2-yl]-phenyl-amine (***3e***)*

IR (cm<sup>−</sup><sup>1</sup> , KBr): 3325, 1632, 1472, 1379, 768, 647; <sup>1</sup> H NMR (CDCl3, 400 MHz): δ 4.06 (s, NH), 7.21 (d, 2H, Ar–H), 7.39 (d, 2H, Ar–H), 7.46 (d, 2H, Ar–H), 7.59(d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 110.5, 119.5, 121.6, 131.6, 131.9, 132.2, 132.5, 141.9, 152.7, 179.3; HRMS; *m*/*z* 286.03 (M<sup>+</sup> ); C15H11ClN2S: calcd. C, 62.82; H, 3.87; N, 9.77; found C, 62.83; H, 3.89; N, 9.78.

**15**

**Entry**

1

2

3

**Phenacyl bromide (1)**

**Phenyl thiourea (2)**

**Product (3a–e)**

**Time (min)**

5

*Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive…*

[4-(4-Chloro-phenyl)-

thiazole-2-yl]-phenyl-amine

10

[4-(4-Methoxy-phenyl)-

thiazole-2-yl]-phenyl-amine

*DOI: http://dx.doi.org/10.5772/intechopen.88243*

[4-(4-Bromo-phenyl)-

thiazole-2-yl]-phenyl-amine

6

**Figure 4.** *Proposed mechanism for TiO2 NPs catalysed thiazole synthesis.*

*Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive… DOI: http://dx.doi.org/10.5772/intechopen.88243*

*Heterocycles - Synthesis and Biological Activities*

IR (cm<sup>−</sup><sup>1</sup>

IR (cm<sup>−</sup><sup>1</sup>

*1.3.4 [4-(4-Fluoro-phenyl)-thiazole-2-yl]-phenyl-amine (***3d***)*

131.6, 131.9, 132.1, 139.7, 151.5, 179.8; HRMS; *m*/*z* 270.06 (M<sup>+</sup>

*1.3.5 [4-(2-Chloro-phenyl)-thiazole-2-yl]-phenyl-amine (***3e***)*

131.9, 132.2, 132.5, 141.9, 152.7, 179.3; HRMS; *m*/*z* 286.03 (M<sup>+</sup>

calcd. C, 62.82; H, 3.87; N, 9.77; found C, 62.83; H, 3.89; N, 9.78.

, KBr): 3340, 1623, 1470, 1389, 766, 665; <sup>1</sup>

calcd. C, 66.65; H, 4.10; N, 10.36; found C, 66.67; H, 4.11; N, 10.37.

, KBr): 3325, 1632, 1472, 1379, 768, 647; <sup>1</sup>

δ 4.09 (s, NH), 7.21 (d, 2H, Ar–H), 7.37 (d, 2H, Ar–H), 7.45 (d, 2H, Ar–H), 7.58(d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 109.8, 121.7, 123.8, 130.6,

δ 4.06 (s, NH), 7.21 (d, 2H, Ar–H), 7.39 (d, 2H, Ar–H), 7.46 (d, 2H, Ar–H), 7.59(d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 110.5, 119.5, 121.6, 131.6,

H NMR (CDCl3, 400 MHz):

); C15H11FN2S:

H NMR (CDCl3, 400 MHz):

); C15H11ClN2S:

**14**

**Figure 4.**

**Figure 3.**

*Synthesis of various substituted thiazole (3a-e).*

*Proposed mechanism for TiO2 NPs catalysed thiazole synthesis.*

**17**

*Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive…*

Quinoxalines are important class of nitrogen containing heterocycles, possessing nitrogen atom at 1,4 position. These heterocycles possess various pharmacological [34–38] and biological properties such as antibiotic (echinomycin, bleomycin), anticancer [39] anti-viral [40], anti-bacterial, antibiotic, and anti-inflammatory. The compounds of quinoxalines used to develop organic semiconductors [41, 42], dehydroannulenes [43], and also used in dyes [44]. Various methods have been reported in literature for the synthesis of quinoxalines, i.e. condensation of 1,2-diketone with phenylene diamine to yield the desired quinoxaline under reflux condition at ambient temperature with various solvents such as benzene, ethanol [45] with use of different catalyst like molecular iodine, copper(II) sulphate, indium(III) chloride, o-iodoxybenzoic acid, ceric ammonium nitrate, silica gel, gallium(III) triflate phosphorus oxychloride, oxidative coupling of epoxides with ene-1,2-diamines [46], 1,4-addition of 1,2-diamines to diazenylbutenes [47], cyclization-oxidation of phenacyl bromides with 1,2-diamines by HClO4-SiO2 [48] and by using solid phase synthesis [49, 50]. Quinoxaline has also been synthesized by the chemical reaction of phenylene diamine and different substituted phenacyl bromides via solid phase [49, 50], synthesis by using different catalyst like 1,4-diazabicyclo [2,2,2]octane, trimethylsilyl chloride, perchloric acid supported on silica, KF-alumina, *β*-cyclodextrin. 1,4-Benzoxazines are important moiety of heterocyclic compounds having considerable biological [51], pharmaceutical [52] and wide range of synthetic utilities. Therefore, new methods should be developed for an efficient protocol for their synthesis. In addition of above information these compounds also served as precursors for the synthesis of many medicinally important drugs [53]. The skeleton of these type of structures are synthesized by the direct intramolecular reductive cyclization of appropriate nitroketones or by intramolecular annulation of 2-aminophenoxy ketones [54]. Benzoxazines are also prepared by the condensation reaction of 2-aminophenols with substituted phenacyl halides [55]. Although, these reported procedures are not specific and general because involvement of more than one-steps, requirement of high temperature, give low to moderate yields and use of commercially unavailable starting material. Hence the discovery of new protocols which leads to an efficient

**2. Synthesis of six-membered heterocylces from phenacyl halides: (1,4-quinoxaline, 1,4-benzoxazines, 1,4-benzothiazines)**

synthetic procedure for synthesis of 1,4-benzoxazine and their derivatives.

chemistry like synthetic organic, medicinal and pharmachemistry.

There are many reported methods in literature for the efficient synthesis for multicomponent reactions (**MCRs**) for the natural products, these methods are of great advantage at atom and step economy level, and these are also environmental friendly. 4*H*-1,4-benzothiazines (having nitrogen and sulphur heteroatom at 1,4 position) are a family of heterocycles possessing number of important biological and pharmacological properties [56]. A compound containing thiazine ring namely 2-benzoyl-7-chloro-3-methyl-5-trifluoromethyl-4*H*-1,4-benzothiazine [57] possessing numerous biological activities like antiemetics, neuroleptics, antihistaminics, antipsychotics, antibacterial, tranquilizers, sedatives, and anticarcinogen. This type of heterocycles has attracted considerable interest of researchers, which leads to the development of synthetic strategies. Therefore, the development and use of new MCRs have been an interesting topic in the areas of various branches of

Although, these reported methods suffered from various limitations such as toxic nature of reagents, excess loading of catalyst, need of high temperature, expensive reagents and complicated work-up to complete the reaction. In present era development of green and sustainable protocols attract the attention of

*DOI: http://dx.doi.org/10.5772/intechopen.88243*

**2.1 Introduction**

#### **2. Synthesis of six-membered heterocylces from phenacyl halides: (1,4-quinoxaline, 1,4-benzoxazines, 1,4-benzothiazines)**

#### **2.1 Introduction**

*Heterocycles - Synthesis and Biological Activities*

[4-(4-Floro-phenyl)-thiazole-2-yl]-phenyl-amine 12

[4-(2-Chloro-phenyl)-

thiazole-2-yl]-phenyl-amine

**16**

**Entry**

4

5

**Table 1.**

*Synthesis of various substituted thiazole (3a–e).*

**Phenacyl bromide (1)**

**Phenyl thiourea (2)**

**Product (3a–e)**

**Time (min)**

9

Quinoxalines are important class of nitrogen containing heterocycles, possessing nitrogen atom at 1,4 position. These heterocycles possess various pharmacological [34–38] and biological properties such as antibiotic (echinomycin, bleomycin), anticancer [39] anti-viral [40], anti-bacterial, antibiotic, and anti-inflammatory. The compounds of quinoxalines used to develop organic semiconductors [41, 42], dehydroannulenes [43], and also used in dyes [44]. Various methods have been reported in literature for the synthesis of quinoxalines, i.e. condensation of 1,2-diketone with phenylene diamine to yield the desired quinoxaline under reflux condition at ambient temperature with various solvents such as benzene, ethanol [45] with use of different catalyst like molecular iodine, copper(II) sulphate, indium(III) chloride, o-iodoxybenzoic acid, ceric ammonium nitrate, silica gel, gallium(III) triflate phosphorus oxychloride, oxidative coupling of epoxides with ene-1,2-diamines [46], 1,4-addition of 1,2-diamines to diazenylbutenes [47], cyclization-oxidation of phenacyl bromides with 1,2-diamines by HClO4-SiO2 [48] and by using solid phase synthesis [49, 50]. Quinoxaline has also been synthesized by the chemical reaction of phenylene diamine and different substituted phenacyl bromides via solid phase [49, 50], synthesis by using different catalyst like 1,4-diazabicyclo [2,2,2]octane, trimethylsilyl chloride, perchloric acid supported on silica, KF-alumina, *β*-cyclodextrin.

1,4-Benzoxazines are important moiety of heterocyclic compounds having considerable biological [51], pharmaceutical [52] and wide range of synthetic utilities. Therefore, new methods should be developed for an efficient protocol for their synthesis. In addition of above information these compounds also served as precursors for the synthesis of many medicinally important drugs [53]. The skeleton of these type of structures are synthesized by the direct intramolecular reductive cyclization of appropriate nitroketones or by intramolecular annulation of 2-aminophenoxy ketones [54]. Benzoxazines are also prepared by the condensation reaction of 2-aminophenols with substituted phenacyl halides [55]. Although, these reported procedures are not specific and general because involvement of more than one-steps, requirement of high temperature, give low to moderate yields and use of commercially unavailable starting material. Hence the discovery of new protocols which leads to an efficient synthetic procedure for synthesis of 1,4-benzoxazine and their derivatives.

There are many reported methods in literature for the efficient synthesis for multicomponent reactions (**MCRs**) for the natural products, these methods are of great advantage at atom and step economy level, and these are also environmental friendly. 4*H*-1,4-benzothiazines (having nitrogen and sulphur heteroatom at 1,4 position) are a family of heterocycles possessing number of important biological and pharmacological properties [56]. A compound containing thiazine ring namely 2-benzoyl-7-chloro-3-methyl-5-trifluoromethyl-4*H*-1,4-benzothiazine [57] possessing numerous biological activities like antiemetics, neuroleptics, antihistaminics, antipsychotics, antibacterial, tranquilizers, sedatives, and anticarcinogen. This type of heterocycles has attracted considerable interest of researchers, which leads to the development of synthetic strategies. Therefore, the development and use of new MCRs have been an interesting topic in the areas of various branches of chemistry like synthetic organic, medicinal and pharmachemistry.

Although, these reported methods suffered from various limitations such as toxic nature of reagents, excess loading of catalyst, need of high temperature, expensive reagents and complicated work-up to complete the reaction. In present era development of green and sustainable protocols attract the attention of

scientists because the use of these above reagents causes many allergic diseases. In this connection of research, various researchers have considerable attention on use of non-hazardous reagents like nanoparticles as heterogeneous catalysts for organic transformations. So, keeping in view these facts of green technology we have tried our effort to develop, a new synthetic strategy for the synthesis of 1,4-quinoxaline, 1,4-benzoxazines, 1,4-benzothiazines catalysed by **TiO2** nanoparticles (**NPs**).

This method is considered to be environment friendly because of use of solid heterogeneous catalyst that provides many advantages such as, ease of handling, non-corrosiveness, high yield, low cost and reusability of the used nanocatalyst.

#### **2.2 General procedure for the synthesis of six-membered heterocycles**

#### *2.2.1 General procedure for the synthesis of 1,4-quinoxaline (***3a** *and* **b***)*

In a 50 ml round bottom flask we took 1,2-phenylenediamine (**1**) (1 mmol) and substituted phenacyl bromide (**2**) (1 mmol) and dissolved both in dichloromenthane-DCM (5 mL). Now add catalytic amount of TiO2 nanoparticles and stirring is continuous at 50° C for appropriate time limit. After completion of reaction, the whole content was filtered fir the removal of nanocatalyst and it was well washed with ethyl acetate (10 mL). This obtained filtrate was concentrated and purified by column chromatography by using hexane/ethylacetate (15% ethyl acetate in hexane) as an eluent to yield desired quinoxaline derivatives in appropriate yields. The nanocatalyst can be recovered after thoroughly washing with ethyl acetate, air dried, and activation at 80° C for 3 h and can reused for further cycles (**Figure 5**).

#### *2.2.2 Spectral data of synthesized compounds*

#### *2.2.2.1 2-Phenylquinoxaline (***3a***)*

Dark yellow solid; M.P: 75–78.3°C; <sup>1</sup> H NMR (400 MHz, CDCl3, TMS = 0 PPM): δ = 7.50–7.58 (m, 3H, ArH), 7.70–7.82 (m, 2H, ArH), 8.14–8.28 (m, 4H, ArH), 9.43 (s, 1H, C3-H) ppm; 13C NMR (100.4 MHz, CDCl3, TMS = 0 PPM): δ = 127.1, 129.19, 129.26, 129.5, 129.6, 130.5, 130.8, 136.4, 141.9, 142.8, 143.6, 152.8 ppm; LCMS (ESI-MS): m/z calcd. for C14H10N2 (M+): 206.24; found: 207.1 (M + H).

#### *2.2.2.2 2-(3-bromophenyl)quinoxaline (***3b***)*

Light brown solid; M.P: 132–133.8°C;1 H NMR (400 MHz, CDCl3, TMS = 0 PPM): *δ* = 7.44–7.48 (t, 1H, ArH), 7.66–7.68 (dd, 1H, ArH), 7.77–7.85 (m, 2H, ArH), 8.14–8.19 (m, 3H, ArH), 8.32–8.40 (t, 1H, ArH), 9.50 (s, 1H, C3-H) ppm; 13C NMR (100 MHz, CDCl3, TMS = 0 PPM): *δ* = 124.4, 126.8, 129.8, 130.6, 130.9, 131.5, 131.6,

**19**

**Figure 6.**

*Synthesis of 1,4-benzoxazines.*

*Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive…*

138.9, 141.8, 142.8, 143.9, 153.2 ppm; LCMS (ESI-MS): m/z calcd. for C14H9BrN2

A catalytic amount of nanoparticles (TiO2) added to the stirring mixture of o-aminophenol (**1**) (1 mmol), substituted phenacyl bromide (**2**) (1 mmol) and triethyl amine (Et3N) (1.1 mmol). After the completion of the reaction the whole content was extracted with Et2O (5X2, 10 mL). After extraction the organic layer was washed with brine (20 mL), and dried over the layer of anhydrous Na2SO4, concentrated and purified by column chromatography by using silica gel and EtOAc/hexane (1:20) (**Figure 6**).

δ = 7.50–7.62 (m, 3H, ArH), 7.76–7.80 (m, 2H, ArH), 8.15–8.29 (m, 4H, ArH), 4.88 (s, 2H, C3-H) ppm; 13C NMR (100.4 MHz, CDCl3, TMS = 77.0 PPM): δ = 127.5, 129.0, 129.2, 129.5, 129.6, 130.1, 130.8, 136.8, 141.5, 142.8, 143.3, 151.8 ppm; LCMS

PPM): *δ* = 7.51–7.58 (t, 1H, ArH), 7.66–7.70 (dd, 1H, ArH), 7.74–7.78 (m, 2H, ArH), 8.16–8.19 (m, 3H, ArH), 8.36–8.40 (t, 1H, ArH), 4.98 (s, 2H, C3-H) ppm; 13C NMR (100 MHz, CDCl3, TMS = 77.0 PPM): *δ* = 74.5, 126.9, 128.8, 130.8, 131.2, 131.5, 131.9, 139.9, 141.9, 142.4, 143.9, 153.2 ppm; LCMS (ESI-MS): m/z calcd for C14H10BrN2

In a round bottom flask the 2-aminobenzenethiol (**1**) (1 mmol), aromatic aldehyde (**2**) (1 mmol), and substituted phenacyl bromide (**3**) (1 mmol), were added in the stirring solution of the DABCO (0.2 mmol) in (Et3N), and stirring was continued for 6 h in

cooled and diluted with DCM (20 mL) and then washed with water. The obtained residue was purified by column chromatography on silica gel (300–400 mesh) with EtOAc and petroleum ether (1:20, v/v) as the eluent to yield the desired product (**Figure 7**).

C. After the completion of the reaction the whole reaction mixture was

(ESI-MS): m/z calcd for C14H10N2 (M+): 206.24; found: 207.1 (M + H).

*2.2.4 General procedure for the synthesis of 1,4-benzothiazines (4e and f)*

H NMR (400 MHz, CDCl3, TMS = 0 PPM):

H NMR (400 MHz, CDCl3, TMS = 0

*2.2.3 General procedure for the synthesis of 1,4-benzoxazines (***3c** *and* **d***)*

*DOI: http://dx.doi.org/10.5772/intechopen.88243*

(M+): 285.14; found: 287.0 (M + 2H).

*2.2.3.1 2-Phenyloxazine (***3c***)*

Brown solid; M.P:88–89.5°C; <sup>1</sup>

*2.2.3.2 2-(3-bromophenyl) oxazine (***3d***)*

(M+): 285.14; found: 287.0 (M + 2H).

an oil bath at 65°

Light yellow solid, M.P: 142–143.8°C;<sup>1</sup>

**Figure 5.** *Synthesis of 1,4-quinoxaline.*

*Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive… DOI: http://dx.doi.org/10.5772/intechopen.88243*

138.9, 141.8, 142.8, 143.9, 153.2 ppm; LCMS (ESI-MS): m/z calcd. for C14H9BrN2 (M+): 285.14; found: 287.0 (M + 2H).

#### *2.2.3 General procedure for the synthesis of 1,4-benzoxazines (***3c** *and* **d***)*

A catalytic amount of nanoparticles (TiO2) added to the stirring mixture of o-aminophenol (**1**) (1 mmol), substituted phenacyl bromide (**2**) (1 mmol) and triethyl amine (Et3N) (1.1 mmol). After the completion of the reaction the whole content was extracted with Et2O (5X2, 10 mL). After extraction the organic layer was washed with brine (20 mL), and dried over the layer of anhydrous Na2SO4, concentrated and purified by column chromatography by using silica gel and EtOAc/hexane (1:20) (**Figure 6**).

#### *2.2.3.1 2-Phenyloxazine (***3c***)*

*Heterocycles - Synthesis and Biological Activities*

is continuous at 50°

dried, and activation at 80°

*2.2.2.1 2-Phenylquinoxaline (***3a***)*

*2.2.2 Spectral data of synthesized compounds*

Dark yellow solid; M.P: 75–78.3°C; <sup>1</sup>

*2.2.2.2 2-(3-bromophenyl)quinoxaline (***3b***)*

Light brown solid; M.P: 132–133.8°C;1

scientists because the use of these above reagents causes many allergic diseases. In this connection of research, various researchers have considerable attention on use of non-hazardous reagents like nanoparticles as heterogeneous catalysts for organic transformations. So, keeping in view these facts of green technology we have tried our effort to develop, a new synthetic strategy for the synthesis of 1,4-quinoxaline, 1,4-benzoxazines, 1,4-benzothiazines catalysed by **TiO2** nanoparticles (**NPs**). This method is considered to be environment friendly because of use of solid heterogeneous catalyst that provides many advantages such as, ease of handling, non-corrosiveness, high yield, low cost and reusability of the used nanocatalyst.

**2.2 General procedure for the synthesis of six-membered heterocycles**

In a 50 ml round bottom flask we took 1,2-phenylenediamine (**1**) (1 mmol) and substituted phenacyl bromide (**2**) (1 mmol) and dissolved both in dichloromenthane-DCM (5 mL). Now add catalytic amount of TiO2 nanoparticles and stirring

whole content was filtered fir the removal of nanocatalyst and it was well washed with ethyl acetate (10 mL). This obtained filtrate was concentrated and purified by column chromatography by using hexane/ethylacetate (15% ethyl acetate in hexane) as an eluent to yield desired quinoxaline derivatives in appropriate yields. The nanocatalyst can be recovered after thoroughly washing with ethyl acetate, air

δ = 7.50–7.58 (m, 3H, ArH), 7.70–7.82 (m, 2H, ArH), 8.14–8.28 (m, 4H, ArH), 9.43 (s, 1H, C3-H) ppm; 13C NMR (100.4 MHz, CDCl3, TMS = 0 PPM): δ = 127.1, 129.19, 129.26, 129.5, 129.6, 130.5, 130.8, 136.4, 141.9, 142.8, 143.6, 152.8 ppm; LCMS

PPM): *δ* = 7.44–7.48 (t, 1H, ArH), 7.66–7.68 (dd, 1H, ArH), 7.77–7.85 (m, 2H, ArH), 8.14–8.19 (m, 3H, ArH), 8.32–8.40 (t, 1H, ArH), 9.50 (s, 1H, C3-H) ppm; 13C NMR (100 MHz, CDCl3, TMS = 0 PPM): *δ* = 124.4, 126.8, 129.8, 130.6, 130.9, 131.5, 131.6,

(ESI-MS): m/z calcd. for C14H10N2 (M+): 206.24; found: 207.1 (M + H).

C for appropriate time limit. After completion of reaction, the

C for 3 h and can reused for further cycles (**Figure 5**).

H NMR (400 MHz, CDCl3, TMS = 0 PPM):

H NMR (400 MHz, CDCl3, TMS = 0

*2.2.1 General procedure for the synthesis of 1,4-quinoxaline (***3a** *and* **b***)*

**18**

**Figure 5.**

*Synthesis of 1,4-quinoxaline.*

Brown solid; M.P:88–89.5°C; <sup>1</sup> H NMR (400 MHz, CDCl3, TMS = 0 PPM): δ = 7.50–7.62 (m, 3H, ArH), 7.76–7.80 (m, 2H, ArH), 8.15–8.29 (m, 4H, ArH), 4.88 (s, 2H, C3-H) ppm; 13C NMR (100.4 MHz, CDCl3, TMS = 77.0 PPM): δ = 127.5, 129.0, 129.2, 129.5, 129.6, 130.1, 130.8, 136.8, 141.5, 142.8, 143.3, 151.8 ppm; LCMS (ESI-MS): m/z calcd for C14H10N2 (M+): 206.24; found: 207.1 (M + H).

#### *2.2.3.2 2-(3-bromophenyl) oxazine (***3d***)*

Light yellow solid, M.P: 142–143.8°C;<sup>1</sup> H NMR (400 MHz, CDCl3, TMS = 0 PPM): *δ* = 7.51–7.58 (t, 1H, ArH), 7.66–7.70 (dd, 1H, ArH), 7.74–7.78 (m, 2H, ArH), 8.16–8.19 (m, 3H, ArH), 8.36–8.40 (t, 1H, ArH), 4.98 (s, 2H, C3-H) ppm; 13C NMR (100 MHz, CDCl3, TMS = 77.0 PPM): *δ* = 74.5, 126.9, 128.8, 130.8, 131.2, 131.5, 131.9, 139.9, 141.9, 142.4, 143.9, 153.2 ppm; LCMS (ESI-MS): m/z calcd for C14H10BrN2 (M+): 285.14; found: 287.0 (M + 2H).

#### *2.2.4 General procedure for the synthesis of 1,4-benzothiazines (4e and f)*

In a round bottom flask the 2-aminobenzenethiol (**1**) (1 mmol), aromatic aldehyde (**2**) (1 mmol), and substituted phenacyl bromide (**3**) (1 mmol), were added in the stirring solution of the DABCO (0.2 mmol) in (Et3N), and stirring was continued for 6 h in an oil bath at 65° C. After the completion of the reaction the whole reaction mixture was cooled and diluted with DCM (20 mL) and then washed with water. The obtained residue was purified by column chromatography on silica gel (300–400 mesh) with EtOAc and petroleum ether (1:20, v/v) as the eluent to yield the desired product (**Figure 7**).

**Figure 6.** *Synthesis of 1,4-benzoxazines.*

**Figure 7.** *Synthesis of 1,4-benzothiazines.*

#### *2.2.4.1 Phenyl (3-phenyl-3,4-dihydro-4H-benzo[b][1,4]thiazin-2-yl) methanone (***4e***)*

Light yellow solid; M.P.: 124–126°C; 1 H NMR (400 MHz, CDCl3): *δ* 7.86 (d, J = 7.5 Hz, 2H), 7.52 (t, J = 7.1 Hz, 1H), 7.41–7.26 (m, 7H), 7.08 (q, J = 7.5 Hz, 2H), 6.70 (t, J = 8.9 Hz, 2H), 5.12 (d, J = 4.8 Hz, 1H), 4.72 (d, J = 5.4 Hz, 1H), 4.45 (s, 1H) ppm; 13C NMR (100.4 MHz, CDCl3) δ47.6, 57.9, 113.8, 115.2, 118.4, 127.4, 127.8, 128.2, 128.4, 128.6, 128.6, 128.7, 133.8, 135.4, 142.4, 142.6, 194.4 ppm; HRMS (ESI) calcd for [C21H17NOS + H] + 332.1109, found 332.1104.

#### *2.2.4.2 (3-Phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-yl)(p-tolyl) methanone (***4f***)*

Brown solid; M.P.: 118–120°C; <sup>1</sup> H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.40 (t, J = 7.2 Hz, 2H), 7.26 (t, J = 8.0 Hz, 3H), 7.10–7.04 (m, 4H), 6.68–6.60 (m, 2H), 5.02 (d, J = 5.7, 1H), 4.58 (d, J = 6.3 Hz, 1H), 4.34 (s, 1H), 2.26 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 47.1, 57.6, 113.6, 115.0, 118.2, 127.4, 127.8, 128.2, 128.4, 128.5, 128.6, 128.7, 133.8, 135.2, 142.2, 142.6, 194.2, 21.5 ppm; HRMS (ESI) calcd. for [C22H19NOS + H] + 346.1266, found 346.1260.

#### **3. Results and discussion**

In this chapter we have tried to develop an efficient protocol for the synthesis of five-membered disubstituted derivatives (**thiazole, 3a–e, Figure 3**) by using TiO2 NPs in moderate to excellent yields from the starting materials phenacyl halides and thioureas. Similarly, six-membered nitrogen containing heterocycles (**quinoxaline derivatives, 3a, b, Figure 5**) from o-phenylenediamines and substituted phenacyl bromides in the presence of TiO2/DCM at 50° C. In the similar way, six-membered nitrogen and oxygen containing heterocycles (**benzoxzines, 3c** and **d, Figure 6**) was

**21**

**Author details**

Dinesh Kumar Jangid\* and Surbhi Dhadda

provided the original work is properly cited.

\*Address all correspondence to: dinu.jangid@gmail.com

Department of Chemistry, University of Rajasthan, Jaipur, Rajasthan, India

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive…*

synthesized under the set of conditions Et3N/TiO2 at room temperature by annulation of o-aminophenols with substituted phenacyl bromides via one pot process. 1,4-benzothiazines are prepared by the reaction of the benzaldehyde, phenacyl halides and 2-aminothiophenols in the presence of set of conditions DABCO, TiO2, Et3N to yield benzothiazine (**4e** and **f, Figure 7**). The TiO2 NPs was characterised by FTIR and SEM

In conclusion, we have developed a green and economic procedure for the synthesis of bioactive five- and six-membered heterocycles. This synthetic methodology allowed us to synthesize products in good to excellent yields, which is irrespective to the functional groups which are present in the starting material. The used protocol is mild and environmental friendly. There are many merits of the used protocol like, low cost of green catalyst, obtaining high yield of products, operational simplicity, and the catalyst can be reused without any significant loss in catalytic property up to four catalytic cycle. These outstanding features of this

images which confirmed the synthesis of TiO2 NPs in the nano range.

*DOI: http://dx.doi.org/10.5772/intechopen.88243*

method make it environmentally friendliness.

**4. Conclusion**

*Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive… DOI: http://dx.doi.org/10.5772/intechopen.88243*

synthesized under the set of conditions Et3N/TiO2 at room temperature by annulation of o-aminophenols with substituted phenacyl bromides via one pot process. 1,4-benzothiazines are prepared by the reaction of the benzaldehyde, phenacyl halides and 2-aminothiophenols in the presence of set of conditions DABCO, TiO2, Et3N to yield benzothiazine (**4e** and **f, Figure 7**). The TiO2 NPs was characterised by FTIR and SEM images which confirmed the synthesis of TiO2 NPs in the nano range.

#### **4. Conclusion**

*Heterocycles - Synthesis and Biological Activities*

*2.2.4.1 Phenyl (3-phenyl-3,4-dihydro-4H-benzo[b][1,4]thiazin-2-yl)* 

*2.2.4.2 (3-Phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-yl)(p-tolyl)* 

(d, J = 7.5 Hz, 2H), 7.52 (t, J = 7.1 Hz, 1H), 7.41–7.26 (m, 7H), 7.08 (q, J = 7.5 Hz, 2H), 6.70 (t, J = 8.9 Hz, 2H), 5.12 (d, J = 4.8 Hz, 1H), 4.72 (d, J = 5.4 Hz, 1H), 4.45 (s, 1H) ppm; 13C NMR (100.4 MHz, CDCl3) δ47.6, 57.9, 113.8, 115.2, 118.4, 127.4, 127.8, 128.2, 128.4, 128.6, 128.6, 128.7, 133.8, 135.4, 142.4, 142.6, 194.4 ppm; HRMS (ESI)

1H), 7.56 (t, J = 7.8 Hz, 1H), 7.40 (t, J = 7.2 Hz, 2H), 7.26 (t, J = 8.0 Hz, 3H), 7.10–7.04 (m, 4H), 6.68–6.60 (m, 2H), 5.02 (d, J = 5.7, 1H), 4.58 (d, J = 6.3 Hz, 1H), 4.34 (s, 1H), 2.26 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 47.1, 57.6, 113.6, 115.0, 118.2, 127.4, 127.8, 128.2, 128.4, 128.5, 128.6, 128.7, 133.8, 135.2, 142.2, 142.6, 194.2, 21.5 ppm; HRMS (ESI) calcd. for [C22H19NOS + H] + 346.1266, found 346.1260.

In this chapter we have tried to develop an efficient protocol for the synthesis of five-membered disubstituted derivatives (**thiazole, 3a–e, Figure 3**) by using TiO2 NPs in moderate to excellent yields from the starting materials phenacyl halides and thioureas. Similarly, six-membered nitrogen containing heterocycles (**quinoxaline derivatives, 3a, b, Figure 5**) from o-phenylenediamines and substituted phenacyl

nitrogen and oxygen containing heterocycles (**benzoxzines, 3c** and **d, Figure 6**) was

H NMR (400 MHz, CDCl3): *δ* 7.86

H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 7.5 Hz,

C. In the similar way, six-membered

*methanone (***4e***)*

*Synthesis of 1,4-benzothiazines.*

**Figure 7.**

*methanone (***4f***)*

**3. Results and discussion**

Brown solid; M.P.: 118–120°C; <sup>1</sup>

bromides in the presence of TiO2/DCM at 50°

Light yellow solid; M.P.: 124–126°C; 1

calcd for [C21H17NOS + H] + 332.1109, found 332.1104.

**20**

In conclusion, we have developed a green and economic procedure for the synthesis of bioactive five- and six-membered heterocycles. This synthetic methodology allowed us to synthesize products in good to excellent yields, which is irrespective to the functional groups which are present in the starting material. The used protocol is mild and environmental friendly. There are many merits of the used protocol like, low cost of green catalyst, obtaining high yield of products, operational simplicity, and the catalyst can be reused without any significant loss in catalytic property up to four catalytic cycle. These outstanding features of this method make it environmentally friendliness.

#### **Author details**

Dinesh Kumar Jangid\* and Surbhi Dhadda Department of Chemistry, University of Rajasthan, Jaipur, Rajasthan, India

\*Address all correspondence to: dinu.jangid@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[5] Correndor CC, Huang ZL, Belfield KD, Morales AR, Bondar MV. Photochromic polymer composites for two-photon 3D optical data storage. Chemistry of Materials. 2007;**19**:5165-5173

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*Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive…*

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[29] Bekaert A, Provot O, Rasolojaona O, Alami M, Brion JD. *N*-Methylpyrrolidin-2-one hydrotribromide (MPHT) a mild reagent for selective bromination of carbonyl compounds: Synthesis of substituted 2-bromo-1-naphtols. Tetrahedron Letters. 2005;**46**:4187-4191

[30] Prakash GKS, Ismail R, Garcia J, Panja C, Rasul G, Mathew T, et al. α-Halogenation of carbonyl compounds: halotrimethylsilane-nitrate salt couple as an efficient halogenating reagent system. Tetrahedron Letters. 2011;**52**:1217-1221

[31] Khan AT, Ali MA, Goswami P, Choudhury LH. A mild and

[32] Kim EH, Koo BS, Song CE, Lee K. Halogenation of aromatic methyl ketones using oxone® and sodium halide. Synthetic Communications.

[33] Venkatachalam N, Palanichamy M, Murugesan V. Sol-gel preparation and characterization of alkaline earth metal doped nano TiO2: Efficient photocatalytic degradation of

4-chlorophenol. Journal of Molecular Catalysis A: Chemical. 2007;**273**:177-185

2001;**31**:3627-3632

regioselective method for α-bromination of β-keto esters and 1,3-diketones using bromodimethylsulfonium bromide (BDMS). The Journal of Organic Chemistry. 2006;**71**:8961-8963

*DOI: http://dx.doi.org/10.5772/intechopen.88243*

[18] Krohnke F, Ellegast K. Selektives Bromieren von Methylketonen und Bromierungen mit Bromketonen. Chemische Berichte. 1953;**86**:1556-1562

[19] Yanovskaya LA, Terentev AP, Belen LI. Chemical Abstracts. 1953;**47**:8032

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[21] Coats SJ, Wasserman HH. The conversion of R-bromo-αdicarbonyls to vicinal tricarbonyls using dimethyldioxirane and base. Tetrahedron Letters. 1995;**36**:7735-7738

[22] Arbuj SS, Waghmode SB, Ramaswamy AV. Photochemical α-bromination of ketones using *N*-bromosuccinimide: A simple, mild and efficient method. Tetrahedron

Letters. 2007;**48**:1411-1415

Letters. 2008;**64**:5191-5199

[24] Das B, Venkateswarlu K, Mahender G, Mahender I. A simple and efficient method for α-bromination of carbonyl compounds using *N*-bromosuccinimide in the presence of silica-supported sodium hydrogen sulfate as a

heterogeneous catalyst. Tetrahedron

[25] Meshram HM, Reddy PN, Sadashiv K, Yadav JS. Amberlyst-15®-promoted efficient 2-halogenation of 1,3-ketoesters and cyclic ketones using N-halosuccinimides. Tetrahedron Letters. 2005;**46**:623-626. DOI: 10.1016/j.tetlet.2004.11.140

Letters. 2005;**46**:3041-3044

[26] Yang D, Yan YL, Lui B. Mild α-halogenation reactions of

1,3-dicarbonyl compounds catalyzed

[23] Pravst I, Zupan M, Stavber S. Halogenation of ketones with *N*-halosuccinimides under solventfree reaction conditions. Tetrahedron

1995;**25**:1045-1051

*Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive… DOI: http://dx.doi.org/10.5772/intechopen.88243*

[18] Krohnke F, Ellegast K. Selektives Bromieren von Methylketonen und Bromierungen mit Bromketonen. Chemische Berichte. 1953;**86**:1556-1562

[19] Yanovskaya LA, Terentev AP, Belen LI. Chemical Abstracts. 1953;**47**:8032

[20] Boyd RE, Rasmussen CR, Press JB. Regiospecific synthesis of unsymmetrical α-bromoketones. Synthetic Communications. 1995;**25**:1045-1051

[21] Coats SJ, Wasserman HH. The conversion of R-bromo-αdicarbonyls to vicinal tricarbonyls using dimethyldioxirane and base. Tetrahedron Letters. 1995;**36**:7735-7738

[22] Arbuj SS, Waghmode SB, Ramaswamy AV. Photochemical α-bromination of ketones using *N*-bromosuccinimide: A simple, mild and efficient method. Tetrahedron Letters. 2007;**48**:1411-1415

[23] Pravst I, Zupan M, Stavber S. Halogenation of ketones with *N*-halosuccinimides under solventfree reaction conditions. Tetrahedron Letters. 2008;**64**:5191-5199

[24] Das B, Venkateswarlu K, Mahender G, Mahender I. A simple and efficient method for α-bromination of carbonyl compounds using *N*-bromosuccinimide in the presence of silica-supported sodium hydrogen sulfate as a heterogeneous catalyst. Tetrahedron Letters. 2005;**46**:3041-3044

[25] Meshram HM, Reddy PN, Sadashiv K, Yadav JS. Amberlyst-15®-promoted efficient 2-halogenation of 1,3-ketoesters and cyclic ketones using N-halosuccinimides. Tetrahedron Letters. 2005;**46**:623-626. DOI: 10.1016/j.tetlet.2004.11.140

[26] Yang D, Yan YL, Lui B. Mild α-halogenation reactions of 1,3-dicarbonyl compounds catalyzed by Lewis acids. The Journal of Organic Chemistry. 2002;**67**:7429-7431

[27] Meshram HM, Reddy PN, Vishnu P, Sadashiv K, Yadav JS. Mild α-halogenation reactions of 1,3-dicarbonyl compounds catalyzed by Lewis acids. The Journal of Organic Chemistry. 2006;**47**:991-995. DOI: 10.1016/j.tetlet.2005.11.141

[28] Lee JC, Park JY, Yoon SY, Bae YH, Lee SJ. Efficient microwave induced direct α-halogenation of carbonyl compounds. Tetrahedron Letters. 2004;**45**:191-193

[29] Bekaert A, Provot O, Rasolojaona O, Alami M, Brion JD. *N*-Methylpyrrolidin-2-one hydrotribromide (MPHT) a mild reagent for selective bromination of carbonyl compounds: Synthesis of substituted 2-bromo-1-naphtols. Tetrahedron Letters. 2005;**46**:4187-4191

[30] Prakash GKS, Ismail R, Garcia J, Panja C, Rasul G, Mathew T, et al. α-Halogenation of carbonyl compounds: halotrimethylsilane-nitrate salt couple as an efficient halogenating reagent system. Tetrahedron Letters. 2011;**52**:1217-1221

[31] Khan AT, Ali MA, Goswami P, Choudhury LH. A mild and regioselective method for α-bromination of β-keto esters and 1,3-diketones using bromodimethylsulfonium bromide (BDMS). The Journal of Organic Chemistry. 2006;**71**:8961-8963

[32] Kim EH, Koo BS, Song CE, Lee K. Halogenation of aromatic methyl ketones using oxone® and sodium halide. Synthetic Communications. 2001;**31**:3627-3632

[33] Venkatachalam N, Palanichamy M, Murugesan V. Sol-gel preparation and characterization of alkaline earth metal doped nano TiO2: Efficient photocatalytic degradation of 4-chlorophenol. Journal of Molecular Catalysis A: Chemical. 2007;**273**:177-185

**22**

*Heterocycles - Synthesis and Biological Activities*

analogues as cytotoxic agents. Bioorganic & Medicinal Chemistry.

using ionic liquid as reusable

[10] Meshram HM, Ramesh P, Kumar GS, Reddy BC. One-pot synthesis of quinoxaline-2-carboxylate derivatives

reaction media. Tetrahedron Letters. 2010;**51**:4313-4316. DOI: 10.1016/j.

[11] Kumbhare RM, Vijay Kumar K, Janaki Ramaiah M, Dadmal T,

Pushpavalli SN, Mukhopadhyay D, et al. Synthesis and biological evaluation of novel Mannich bases of 2-arylimidazo [2, 1-b] benzothiazoles as potential anti-cancer agents. European Journal of Medicinal Chemistry. 2011;**46**:4258- 4266. DOI: 10.1016/j.ejmech.2011.06.031

[12] Larock RC. Comprehensive Organic Transformations. 3rd ed. New York:

[14] Lewis JR. Nitrile-containing natural products. Natural Product Reports.

[15] Lednicer D, Mitscher LA, Georg GI. Organic Chemistry of Drug Synthesis. New York: Wiley; 1990. pp. 95-97

[16] Ei-Subbagh HI, AI-Obaid AM. 2,4-Disubstituted thiazoles II. A novel class of antitumor agents, synthesis and biological evaluation. European Journal of Medicinal Chemistry.

[17] King LC, Ostrum GK. Selective bromination with Copper(II) bromide. The Journal of Organic Chemistry.

2002;**10**:3481-3487

tetlet.2010.05.099

VCH; 1999. p. 709

1982;**29**:327-328

1999;**16**:389-416

1996;**31**:1017-1021

1964;**29**:3459-3461

[13] Talegaonkar J, Mukhija S, Boparai KS. Determination of thiosemicarbazones by reaction with ω-bromoacetophenone. Talanta.

[1] Gupta RR, Kumar M, Gupta V. Nomenclature of heterocycles. Journal of Heterocyclic Chemistry. 1998;**1**:3-38. DOI: 10.1007/978-3-642-72276-9\_2

[2] Joshi RC. Mild and efficient one pot synthesis of imidazolines and benzimidazoles from aldehydes.

[3] Fox HH, Bogert MT. A review of biologically active benzothiazole, thiazole and pyridine derivatives. Journal of the American Chemical

Society. 1993;**61**:2013-2017

[4] Burger A, Sawhney SN. Antimalarials. III. Benzothiazole amino alcohols. Journal of Medicinal

Chemistry. 1968;**11**:270-273

KD, Morales AR, Bondar MV. Photochromic polymer composites for two-photon 3D optical data storage. Chemistry of Materials.

Molecules. 2003;**8**:793-865

2007;**19**:5165-5173

1988. p. 151

[5] Correndor CC, Huang ZL, Belfield

[6] Erian AM, Sherif SM, Gaber HM. The chemistry of α-haloketones and their utility in heterocyclic synthesis.

[7] Bolton R. In: Price D, Iddon B, Wakefield BJ, editors. Bromine Compounds: Chemistry and Applications. Amsterdam: Elsevier;

[8] Arabaci G, Guo XC, Beebe KD, Coggeshall KM, Pei D.

1999;**121**:5085-5086

α-haloacetophenone derivatives as photoreversible covalent inhibitors of protein tyrosine phosphatases. Journal of the American Chemical Society.

[9] Ishida J, Ohtsu H, Tachibana Y, Nakanishi Y, Bastow KF, Nagai M, et al. Antitumor agents. Part 214: Synthesis and evaluation of curcumin

E-Journal of Chemistry. 2007;**4**:606-610

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[35] Sakata G, Makino K, Kurasawa Y. Recent progress in the quinoline chemistry. Synthesis and biological activity. Heterocycles. 1998;**27**:2481-2515

[36] Gomtsyan A, Bayburt EK, Schmidt RG, Zheng GZ, Perner RJ, Didomenico S, et al. Novel transient receptor potential vanilloid 1 receptor antagonists for the treatment of pain:Structure−activity relationships for ureas with quinoline, isoquinoline, quinazoline, phthalazine, quinoxaline, and cinnoline moieties. Journal of Medicinal Chemistry. 2005;**48**:744-752

[37] Seitz LE, Suling WJ, Reynolds RC. Synthesis and antimycobacterial activity of pyrazine and quinoxaline derivatives. Journal of Medicinal Chemistry. 2002;**45**:5604-5606

[38] Discovery of a new series of centrally active tricyclic isoxazoles combining serotonin (5-HT) reuptake inhibition with α2-adrenoceptor blocking activity. Journal of Medicinal Chemistry. 2005;**48**:2019

[39] Lindsley CW, Zhao Z, Leister WH, Robinson RG, Barnell SF, Defeozones D, et al. Allosteric Akt (PKB) inhibitors: Discovery and SAR of isozyme selective inhibitors. Bioorganic & Medicinal Chemistry Letters. 2005;**15**:761-764

[40] Loriga M, Piras S, Sanna P, Paglietti G. 2-[aminobenzoates] and 2-[aminobenzoylglutamate] quinozalines as classical antifolate agents. Synthesis and evaluation of in vitro anticancer, anti-HIV and antifungal activity. Farmaco. 1997;**52**:157-166

[41] Dailey S, Feast JW, Peace RJ, Sage IC, Till S, Wood EL. Synthesis and

device characterization of side-chain polymer electron transport materials for organic semiconductor applications. Journal of Materials Chemistry. 2001;**11**:2238-2243

[42] O'Brien D, Weaver MS, Lidzey DG, DDC B. Use of poly (phenyl quinoxaline) as an electron transport material in polymer light-emitting diodes. Applied Physics Letters. 1996;**69**:881-883

[43] Ott S, Faust R. Quinoxalinodehydroannulenes: A novel class of carbon-rich materials. Synlett. 2004:1509-1512

[44] Brock ED, Lewis DM, Yousaf TI, Harper HH. WO 9951688. USA: The Procter & Gamble Company; 1999

[45] Brown DJ. The Chemistry of Heterocyclic Compounds Quinoxalines: Supplement II. New Jersey: John Wiley & Sons; 2004

[46] Antoniotti S, Dunach E. Direct and catalytic synthesis of quinoxaline derivatives from epoxides and ene-1,2-diamines. Tetrahedron Letters. 2002;**43**:3971-3973. DOI: 10.1016/ S0040-4039(02)00715-3

[47] Aparicio D, Attanasi OA, Filippone P, Ignacio R, Lillini S, Mantellini F, et al. Straightforward access to pyrazines, piperazinones, and quinoxalines by reactions of 1,2-diaza-1,3-butadienes with 1,2-diamines under solution, solvent-free, or solid-phase conditions. The Journal of Organic Chemistry. 2006;**71**:5897-5905. DOI: 10.1021/ jo060450v

[48] Das B, Venkateswarlu K, Suneel K, Majhi A. An efficient and convenient protocol for the synthesis of quinoxalines and dihydropyrazines via cyclization–oxidation processes using HClO4·SiO2 as a heterogeneous recyclable catalyst. Tetrahedron Letters. 2007;**48**:5371-5374. DOI: 10.1016/j.tetlet.2007.06.036

**25**

*Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive…*

2-amino-4H-benzothiazines. Organic Letters. 2000;**2**:3667-3670. DOI:

[57] Wu J, Shang Y, Wang C, He X, Yan Z, Hu M, et al. Synthesis of 3,4-dihydro-2H-1,4-benzo[b]thiazine derivatives via DABCO-catalyzed one-pot threecomponent condensation reactions. RSC Advances. 2013;**3**(14):4643-4651. DOI:

10.1021/o1006580m

10.1039/C3RA00123G

*DOI: http://dx.doi.org/10.5772/intechopen.88243*

[49] Wu Z, Ede NJ, et al. Solid-phase synthesis of quinoxalines on SynPhase™

Lanterns. Tetrahedron Letters. 2001;**42**:8115-8118. DOI: 10.1016/

[50] Singh SK, Gupta P, Duggineni S, Kundu B. Solid phase synthesis of quinoxalines. Synlett. 2003;**14**:2147- 2150. DOI: 10.1055/s-2003-42065

[51] Yang W, Wang Y, Ma Z, Golla R, Stouch T, Seethala R, et al. Synthesis and structure-activity relationship of 3-arylbenzoxazines as selective estrogen receptor b agonists. Bioorganic

& Medicinal Chemistry Letters. 2004;**14**:2327-2330. DOI: 10.1016/j.

J, Mani S. Design, synthesis and biological evaluation of 2*H*-benzo[b] [1,4]oxazine derivatives as hypoxia targeted compounds for cancer therapeutics. Bioorganic & Medicinal Chemistry Letters. 2009;**19**:4204-4206.

DOI: 10.1016/j.bmcl.2009.05.110

[53] Satoh K, Inenaga M, Kanai K. Synthesis of a key intermediate of levofloxacin via enantioselective hydrogenation catalyzed by iridium(I) complexes. Tetrahedron: Asymmetry. 1998;**9**:2657-2662. DOI: 10.1016/

[54] Chiccara F, Novellino E. Some new aspects on the chemistry of 1,4-benzoxazines. Journal of Heterocyclic Chemistry. 1985;**22**:1021- 1023. DOI: 10. 1002/jhet.5570220418

[55] Sabitha G, Subba Rao AV. Synthesis of 3-arylcoumarins, 2-aroylbenzofurans and 3-aryl-2*H*-1,4-benzoazines under phasetransfer catalysis conditions. Synthetic

10.1080/00397918708077315

[56] Hari A, Miller BL. Rapid and efficient synthesis of

Communications. 1987;**17**:341-354. DOI:

S0957-4166(98)00276-6

[52] Das BC, Madhukumar AV, Anguiano

bmcl.2004.01.099

S0040-4039(01)01733-6

*Phenacyl Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive… DOI: http://dx.doi.org/10.5772/intechopen.88243*

[49] Wu Z, Ede NJ, et al. Solid-phase synthesis of quinoxalines on SynPhase™ Lanterns. Tetrahedron Letters. 2001;**42**:8115-8118. DOI: 10.1016/ S0040-4039(01)01733-6

*Heterocycles - Synthesis and Biological Activities*

Synthesis and antimicrobial activities of some novel quinoxalinone derivatives.

device characterization of side-chain polymer electron transport materials for organic semiconductor applications.

[42] O'Brien D, Weaver MS, Lidzey DG, DDC B. Use of poly (phenyl quinoxaline) as an electron transport material in polymer light-emitting diodes. Applied Physics Letters. 1996;**69**:881-883

Quinoxalinodehydroannulenes: A novel class of carbon-rich materials. Synlett.

[44] Brock ED, Lewis DM, Yousaf TI, Harper HH. WO 9951688. USA: The Procter & Gamble Company; 1999

[45] Brown DJ. The Chemistry of Heterocyclic Compounds Quinoxalines: Supplement II. New Jersey: John Wiley

[46] Antoniotti S, Dunach E. Direct and catalytic synthesis of quinoxaline derivatives from epoxides and ene-1,2-diamines. Tetrahedron Letters. 2002;**43**:3971-3973. DOI: 10.1016/

[47] Aparicio D, Attanasi OA, Filippone P, Ignacio R, Lillini S, Mantellini F, et al. Straightforward access to pyrazines, piperazinones, and quinoxalines by reactions of 1,2-diaza-1,3-butadienes with 1,2-diamines under solution, solvent-free, or solid-phase conditions. The Journal of Organic Chemistry. 2006;**71**:5897-5905. DOI: 10.1021/

S0040-4039(02)00715-3

[48] Das B, Venkateswarlu K, Suneel K, Majhi A. An efficient and convenient protocol for the synthesis of quinoxalines and dihydropyrazines via cyclization–oxidation processes using HClO4·SiO2 as a heterogeneous recyclable catalyst. Tetrahedron Letters. 2007;**48**:5371-5374. DOI: 10.1016/j.tetlet.2007.06.036

Journal of Materials Chemistry.

2001;**11**:2238-2243

[43] Ott S, Faust R.

2004:1509-1512

& Sons; 2004

jo060450v

[34] Ali MM, Ismail MMF, EI-Gabby MSA, Zahran MA, Ammar YA.

[35] Sakata G, Makino K, Kurasawa Y. Recent progress in the quinoline

biological activity. Heterocycles.

[36] Gomtsyan A, Bayburt EK, Schmidt RG, Zheng GZ, Perner RJ, Didomenico S, et al. Novel transient receptor potential vanilloid 1 receptor antagonists for the treatment of pain:Structure−activity relationships for ureas with quinoline, isoquinoline, quinazoline, phthalazine, quinoxaline, and cinnoline moieties. Journal of Medicinal Chemistry. 2005;**48**:744-752

[37] Seitz LE, Suling WJ, Reynolds RC. Synthesis and antimycobacterial activity of pyrazine and quinoxaline derivatives.

Journal of Medicinal Chemistry.

[38] Discovery of a new series of centrally active tricyclic isoxazoles combining serotonin (5-HT) reuptake inhibition with α2-adrenoceptor blocking activity. Journal of Medicinal

[39] Lindsley CW, Zhao Z, Leister WH, Robinson RG, Barnell SF, Defeozones D, et al. Allosteric Akt (PKB) inhibitors: Discovery and SAR of isozyme selective inhibitors. Bioorganic & Medicinal Chemistry Letters. 2005;**15**:761-764

Chemistry. 2005;**48**:2019

[40] Loriga M, Piras S, Sanna P, Paglietti G. 2-[aminobenzoates] and 2-[aminobenzoylglutamate] quinozalines as classical antifolate agents. Synthesis and evaluation of in vitro anticancer, anti-HIV and antifungal activity. Farmaco. 1997;**52**:157-166

[41] Dailey S, Feast JW, Peace RJ, Sage IC, Till S, Wood EL. Synthesis and

2002;**45**:5604-5606

Molecules. 2000;**5**:864-873

chemistry. Synthesis and

1998;**27**:2481-2515

**24**

[50] Singh SK, Gupta P, Duggineni S, Kundu B. Solid phase synthesis of quinoxalines. Synlett. 2003;**14**:2147- 2150. DOI: 10.1055/s-2003-42065

[51] Yang W, Wang Y, Ma Z, Golla R, Stouch T, Seethala R, et al. Synthesis and structure-activity relationship of 3-arylbenzoxazines as selective estrogen receptor b agonists. Bioorganic & Medicinal Chemistry Letters. 2004;**14**:2327-2330. DOI: 10.1016/j. bmcl.2004.01.099

[52] Das BC, Madhukumar AV, Anguiano J, Mani S. Design, synthesis and biological evaluation of 2*H*-benzo[b] [1,4]oxazine derivatives as hypoxia targeted compounds for cancer therapeutics. Bioorganic & Medicinal Chemistry Letters. 2009;**19**:4204-4206. DOI: 10.1016/j.bmcl.2009.05.110

[53] Satoh K, Inenaga M, Kanai K. Synthesis of a key intermediate of levofloxacin via enantioselective hydrogenation catalyzed by iridium(I) complexes. Tetrahedron: Asymmetry. 1998;**9**:2657-2662. DOI: 10.1016/ S0957-4166(98)00276-6

[54] Chiccara F, Novellino E. Some new aspects on the chemistry of 1,4-benzoxazines. Journal of Heterocyclic Chemistry. 1985;**22**:1021- 1023. DOI: 10. 1002/jhet.5570220418

[55] Sabitha G, Subba Rao AV. Synthesis of 3-arylcoumarins, 2-aroylbenzofurans and 3-aryl-2*H*-1,4-benzoazines under phasetransfer catalysis conditions. Synthetic Communications. 1987;**17**:341-354. DOI: 10.1080/00397918708077315

[56] Hari A, Miller BL. Rapid and efficient synthesis of

2-amino-4H-benzothiazines. Organic Letters. 2000;**2**:3667-3670. DOI: 10.1021/o1006580m

[57] Wu J, Shang Y, Wang C, He X, Yan Z, Hu M, et al. Synthesis of 3,4-dihydro-2H-1,4-benzo[b]thiazine derivatives via DABCO-catalyzed one-pot threecomponent condensation reactions. RSC Advances. 2013;**3**(14):4643-4651. DOI: 10.1039/C3RA00123G

**Chapter 3**

**Abstract**

**1. Introduction**

antioxidant, etc. [2, 3].

**27**

Amidoxime Derivatives with Local

Оur task in the field of new derivatives of amidoximes was the elaboration for new medication with increased activity and lower toxicity than medications used in practice. Here are the results of the search for new painkillers and antitubercular and antidiabetic drugs in the class of amidoxime derivatives. Nitrous derivatives of α-chloro-α-isonitrosoacetone, *O*-aroyl-β-aminopropioamidoximes, and 3-[β-(piperidine-1-yl)]ethyl-5-aryl-1,2,4-oxadiazoles were tested for conduction, infiltration, and terminal anesthesia. Among them hit compounds were discovered. The search for new anti-TB drugs is executed in the world. Salts and bases of *O*-aroylation

propioamidoximes during *in vitro* antitubercular screening for DS, DR, and MDR strains of *M. tuberculosis* manifest themselves as highly active competitive compounds. In the series of the derivatives of β-aminopropioamidoximes, a search for new antidiabetic drugs was done. The compounds with pronounced antidiabetic properties were revealed. The obtained data of the most promising samples with a preliminary assessment of their average toxic dose in animals can be used in further *in vivo* testing of infiltration anesthesia conditions, of antidiabetic properties, and at

**Keywords:** nitrous derivatives of α-chloro-α-isonitrosoacetone, bases and salts of *O*-aroyl-β-aminopropioamidoximes, 3-(β-amino)ethyl-5-aryl-1,2,4-oxadiazoles,

First of all, researchers' interest in amidoximes is due to the possibility of their synthetic modification according to the reaction groups NOH and NH2. The largest number of derivatives was obtained as a result of acylation reactions at the O-atom of the NOH group and subsequent transformations involving the NH2 fragment to 1,2,4-oxadiazoles [1]. In most cases, amidoxime derivatives, including heterocyclic radicals, under standard conditions are stable, allowing their structural identification, and withstand storage and biological screening. Arrays of data were obtained on their diverse biological activity: antitubercular, local anesthetic, antidiabetic,

The rational use of drugs is one of the urgent problems of modern medicine. A doctor of any profile most often faces the need to eliminate and prevent pain.

products of β-(thiomorpholin-1-yl) and β-(4-methylpiperazin-1-yl)

the development of doses and new treatment regimens for TB.

local anesthetics, *in vitro* antitubercular, antidiabetic screening

Anesthetic, Antitubercular, and

Antidiabetic Activity

*and Kaldybay Praliyev*

*Lyudmila Kayukova, Umirzak Jussipbekov*

#### **Chapter 3**

## Amidoxime Derivatives with Local Anesthetic, Antitubercular, and Antidiabetic Activity

*Lyudmila Kayukova, Umirzak Jussipbekov and Kaldybay Praliyev*

#### **Abstract**

Оur task in the field of new derivatives of amidoximes was the elaboration for new medication with increased activity and lower toxicity than medications used in practice. Here are the results of the search for new painkillers and antitubercular and antidiabetic drugs in the class of amidoxime derivatives. Nitrous derivatives of α-chloro-α-isonitrosoacetone, *O*-aroyl-β-aminopropioamidoximes, and 3-[β-(piperidine-1-yl)]ethyl-5-aryl-1,2,4-oxadiazoles were tested for conduction, infiltration, and terminal anesthesia. Among them hit compounds were discovered. The search for new anti-TB drugs is executed in the world. Salts and bases of *O*-aroylation products of β-(thiomorpholin-1-yl) and β-(4-methylpiperazin-1-yl) propioamidoximes during *in vitro* antitubercular screening for DS, DR, and MDR strains of *M. tuberculosis* manifest themselves as highly active competitive compounds. In the series of the derivatives of β-aminopropioamidoximes, a search for new antidiabetic drugs was done. The compounds with pronounced antidiabetic properties were revealed. The obtained data of the most promising samples with a preliminary assessment of their average toxic dose in animals can be used in further *in vivo* testing of infiltration anesthesia conditions, of antidiabetic properties, and at the development of doses and new treatment regimens for TB.

**Keywords:** nitrous derivatives of α-chloro-α-isonitrosoacetone, bases and salts of *O*-aroyl-β-aminopropioamidoximes, 3-(β-amino)ethyl-5-aryl-1,2,4-oxadiazoles, local anesthetics, *in vitro* antitubercular, antidiabetic screening

#### **1. Introduction**

First of all, researchers' interest in amidoximes is due to the possibility of their synthetic modification according to the reaction groups NOH and NH2. The largest number of derivatives was obtained as a result of acylation reactions at the O-atom of the NOH group and subsequent transformations involving the NH2 fragment to 1,2,4-oxadiazoles [1]. In most cases, amidoxime derivatives, including heterocyclic radicals, under standard conditions are stable, allowing their structural identification, and withstand storage and biological screening. Arrays of data were obtained on their diverse biological activity: antitubercular, local anesthetic, antidiabetic, antioxidant, etc. [2, 3].

The rational use of drugs is one of the urgent problems of modern medicine. A doctor of any profile most often faces the need to eliminate and prevent pain. With pain of varying intensities, adequate pain relief reduces the patient's tension and fear, prevents him from forming a negative attitude to medical manipulations, and protects the nervous system of the doctor and patient, providing better medical care. The search for new painkillers with increased activity and lower toxicity than painkillers used in practice is one of the tasks of modern medical chemistry. We developed new β-aminopropioamidoximes and studied their neurotropic properties. Herein we present results from a study of the local anesthetic activities of three chemical groups of new amidoxime derivatives [4].

The first group includes derivatives of α-chloro-α-isonitrosoacetone such as 3 acetyl-5,5-bis(hydroxymethyl)-5,6-dihydro-4*H*-1,2,4-oxadiazine (**1**) and the *anti*isomer of *N*-(4-methylphenyl)acetylformamidoxime thiosemicarbazone (**2**). The second group includes the hydrochlorides of *O*-aroyl-β-aminopropioamidoximes with piperidine (**3**), morpholine (**4**–**6**), and benzimidazole (**7** and **8**) in the β-position. The third group consists of 3-[β-(piperidin-1-yl)]ethyl-5-*p*-tolyl-1,2,4-oxadiazole (**9**)

*Amidoxime Derivatives with Local Anesthetic, Antitubercular, and Antidiabetic Activity*

The local anesthetic activity of **1**–**10** was studied in three types of anesthesia, i.e., infiltration, conduction, and terminal. The reference drugs were trimecaine, lidocaine, novocaine, and kazcaine [hydrochloride of 1-(2-ethoxyethyl)-4-ethynyl-4-

> **Duration of complete anesthesia (М m), min**

 22.6 1.4\* 10.0 2.5\*\* 40.0 2.7\* 28.0 2.2\*\* 14.4 0.4\*\*\* 29.1 2.2\*\* 28.8 3.7\*\*\*\* 15.0 0.0\* 28.0 4.9\*\*\* 31.4 1.4\*\* 18.3 7.7 55.0 1.8\*\*\*\* 30.6 1.3\* 20.8 2.4\*\*\*\* 55.8 2.1\*\* 21.0 2.4\* 8.3 2.7 34.1 0.8\* 31.0 1.2\*\*\*\* 20.0 2.8\* 45.8 2.5\*\*\*\* 34.0 1.15\* 25.0 2.8\*\* 55.8 2.1\*\* 34.1 0.7\*\* 25.0 0.3\* 58.3 2.7\* 36.0 0.0\* 85.0 0.8\*\*\*\* 125.0 1.8\*\* Trimecaine 34.1 0.5 30.0 1.7 44.1 1.7 Lidocaine 32.3 2.3 25.8 0.8 54.5 2.3 Novocaine 30.0 0.2 10.0 0.0 22.0 0.1 Kazkain 31.1 1.2 25.0 2.5 75.0 0.7

*Activity and duration of action of compounds 1–10 (0.5% concentration) for infiltration anesthesia.*

**Total duration of anesthesia (М m), min**

and 3-[β-(piperidin-1-yl)]ethyl-5-*m*-chlorophenyl-1,2,4-oxadiazole (**10**).

benzoyloxypiperidine] (**Tables 1**–**3**).

*DOI: http://dx.doi.org/10.5772/intechopen.90002*

**Compound Anesthesia index**

*\**

**Table 1.**

**29**

*Compared to trimecaine. \*\*Compared with lidocaine. \*\*\*In comparison with novocaine. \*\*\*\*Compared to cascaine.*

**(М m)**

Tuberculosis (TB) is the leading cause of death and morbidity in more than one third of the world's population. Of the 56.4 million deaths worldwide due to the 10 leading causes in 2016, tuberculosis ranked 10th, from which 1.4 million people died [5].

In May 2014, the World Health Organization (WHO) approved a new global TB control strategy "End TB". This strategy marks a critical shift from tuberculosis control to ending the epidemic by 2035. The "End TB" strategy emphasizes the need for innovation to accelerate progress by optimizing existing ones in the short term and introducing new innovative modes in the long term [6]. In order to reduce the duration of treatment, the rapid development of drug resistance and toxic and side effects of existing anti-TB drugs, and to reduce the cost of extremely expensive treatment of TB (DS, MDR, XDR), the world is searching for new anti-TB drugs. We have synthesized the salts and bases of the *O*-aroylation products of β-(thiomorpholin-1-yl) and β-(4-methylpiperazin-1-yl)propioamidoximes, containing in the β-position pharmacophore fragments of 1-methylpiperazine and thiomorpholine. *In vitro* antitubercular screening of β-aminopropioamidoxime derivatives in the DS, DR, and MDR strains of *M. tuberculosis* revealed highly active competitive compounds which are less toxic than rifampicin and isoniazid with activity significantly exceeding the activity of the reference preparations. It is assumed that these compounds may be the subject of subsequent trials in the development of doses and new treatment regimens for TB [7, 8].

Diabetes is on the rise across the globe. Presently every 7 seconds someone is estimated to die from diabetes or its complications. This is against the background of a global diabetes prevalence of 8.8% of the world population in 2017. The prevalence is expected to further increase to 9.9% by the year 2045. In total numbers, this reflects a population of 424.9 million people with diabetes worldwide in 2017 with an estimate of a 48% increase to 628.6 million people for the year 2045 [9]. Due to the urgency of the problem of diabetes in the world, a search is underway for new antidiabetic drugs. The antidiabetic activity of amidoxime derivatives is known [10, 11]. We conducted *in vitro* testing of derivatives of β-aminopropioamidoximes: bases and pharmacologically acceptable salts of *O*-aroyl-β-(morpholin-1-yl) propioamidoxime and 5-aryl-3-β-(piperidin-1-yl and morpholin-1-yl)ethyl-1,2,4 oxadiazoles with respect to their ability to inhibit the activity of α-amylase and α-glucosidase enzymes. Identified compounds with pronounced antidiabetic properties must be noted; a series of 3,5-disubstituted 1,2,4-oxadiazoles is more active than a series of *O*-aroyl-β-aminopropioamidoximes [12].

The data obtained can be used in further *in vivo* testing of the antidiabetic properties of the most promising samples with a preliminary assessment of their average toxic dose in animals.

#### **2. Local anesthetic activity of new amidoxime derivatives**

Herein we present results from a study of the local anesthetic activities of three chemical groups of new amidoxime derivatives (**1**–**10**) [4].

*Amidoxime Derivatives with Local Anesthetic, Antitubercular, and Antidiabetic Activity DOI: http://dx.doi.org/10.5772/intechopen.90002*

The first group includes derivatives of α-chloro-α-isonitrosoacetone such as 3 acetyl-5,5-bis(hydroxymethyl)-5,6-dihydro-4*H*-1,2,4-oxadiazine (**1**) and the *anti*isomer of *N*-(4-methylphenyl)acetylformamidoxime thiosemicarbazone (**2**). The second group includes the hydrochlorides of *O*-aroyl-β-aminopropioamidoximes with piperidine (**3**), morpholine (**4**–**6**), and benzimidazole (**7** and **8**) in the β-position. The third group consists of 3-[β-(piperidin-1-yl)]ethyl-5-*p*-tolyl-1,2,4-oxadiazole (**9**) and 3-[β-(piperidin-1-yl)]ethyl-5-*m*-chlorophenyl-1,2,4-oxadiazole (**10**).

The local anesthetic activity of **1**–**10** was studied in three types of anesthesia, i.e., infiltration, conduction, and terminal. The reference drugs were trimecaine, lidocaine, novocaine, and kazcaine [hydrochloride of 1-(2-ethoxyethyl)-4-ethynyl-4 benzoyloxypiperidine] (**Tables 1**–**3**).


*Compared to trimecaine.*

*\*\*Compared with lidocaine.*

*\*\*\*In comparison with novocaine. \*\*\*\*Compared to cascaine.*

#### **Table 1.**

*Activity and duration of action of compounds 1–10 (0.5% concentration) for infiltration anesthesia.*

With pain of varying intensities, adequate pain relief reduces the patient's tension and fear, prevents him from forming a negative attitude to medical manipulations, and protects the nervous system of the doctor and patient, providing better medical care. The search for new painkillers with increased activity and lower toxicity than painkillers used in practice is one of the tasks of modern medical chemistry. We developed new β-aminopropioamidoximes and studied their neurotropic properties. Herein we present results from a study of the local anesthetic activities of three

Tuberculosis (TB) is the leading cause of death and morbidity in more than one third of the world's population. Of the 56.4 million deaths worldwide due to the 10 leading causes in 2016, tuberculosis ranked 10th, from which 1.4 million people

In May 2014, the World Health Organization (WHO) approved a new global TB control strategy "End TB". This strategy marks a critical shift from tuberculosis control to ending the epidemic by 2035. The "End TB" strategy emphasizes the need for innovation to accelerate progress by optimizing existing ones in the short term and introducing new innovative modes in the long term [6]. In order to reduce the duration of treatment, the rapid development of drug resistance and toxic and side effects of existing anti-TB drugs, and to reduce the cost of extremely expensive treatment of TB (DS, MDR, XDR), the world is searching for new anti-TB drugs.

We have synthesized the salts and bases of the *O*-aroylation products of β-(thiomorpholin-1-yl) and β-(4-methylpiperazin-1-yl)propioamidoximes, containing in the β-position pharmacophore fragments of 1-methylpiperazine and thiomorpholine. *In vitro* antitubercular screening of β-aminopropioamidoxime derivatives in the DS, DR, and MDR strains of *M. tuberculosis* revealed highly active competitive compounds which are less toxic than rifampicin and isoniazid with activity significantly exceeding the activity of the reference preparations. It is assumed that these compounds may be the subject of subsequent trials in the

development of doses and new treatment regimens for TB [7, 8].

Diabetes is on the rise across the globe. Presently every 7 seconds someone is estimated to die from diabetes or its complications. This is against the background of a global diabetes prevalence of 8.8% of the world population in 2017. The prevalence is expected to further increase to 9.9% by the year 2045. In total numbers, this reflects a population of 424.9 million people with diabetes worldwide in 2017 with an estimate of a 48% increase to 628.6 million people for the year 2045 [9]. Due to the urgency of the problem of diabetes in the world, a search is underway for new antidiabetic drugs. The antidiabetic activity of amidoxime derivatives is known [10, 11]. We conducted *in vitro* testing of derivatives of β-aminopropioamidoximes:

bases and pharmacologically acceptable salts of *O*-aroyl-β-(morpholin-1-yl) propioamidoxime and 5-aryl-3-β-(piperidin-1-yl and morpholin-1-yl)ethyl-1,2,4 oxadiazoles with respect to their ability to inhibit the activity of α-amylase and α-glucosidase enzymes. Identified compounds with pronounced antidiabetic properties must be noted; a series of 3,5-disubstituted 1,2,4-oxadiazoles is more

The data obtained can be used in further *in vivo* testing of the antidiabetic properties of the most promising samples with a preliminary assessment of their

Herein we present results from a study of the local anesthetic activities of three

active than a series of *O*-aroyl-β-aminopropioamidoximes [12].

**2. Local anesthetic activity of new amidoxime derivatives**

chemical groups of new amidoxime derivatives (**1**–**10**) [4].

average toxic dose in animals.

**28**

chemical groups of new amidoxime derivatives [4].

*Heterocycles - Synthesis and Biological Activities*

died [5].


This compound also turned out to be more active than the other tested com-

Compounds **5** and **7**–**9** had longer durations of action than novocaine, shorter than trimecaine, and essentially the same as lidocaine and kazcaine. The duration of total anesthesia of **4** was longer than that of novocaine and slightly shorter than that of the other reference drugs. The durations of total anesthesia for **1** and **4** (10.0 and

**Table 2** presents results from a study of conduction anesthesia by **1**–**10**. Like in the preceding series of tests, **10** had the highest activity. Its anesthesia index was greater than those of trimecaine, lidocaine, and novocaine and equal to that of kazcaine. Compounds **1**–**5** and **7**–**9** were rather active. Their anesthesia indices were greater than those of trimecaine, novocaine, and lidocaine. However, they were less than that of kazcaine. Compound **6** was less active than the reference drugs. Like in the preceding series of tests, the durations of total anesthesia of the studied compounds were compared. **Table 2** shows that all compounds **1**–**10** had total anesthesia duration indices that were shorter than that of kazcaine although **3**, **4**, and **7**–**10** had durations of action longer than those of novocaine, lidocaine, and

Compounds **1**–**10** in terminal anesthesia were weaker and shorter acting than dicaine (**Table 3**). However, not one of these compounds exhibited an irritating

Thus, it was shown that amidoxime derivatives **1**–**10** exhibited anesthetic effects that were greater than those of the reference drugs in conduction and infiltration

anesthesia. The 1,2,4-oxadiazoles **9** and **10** and to a lesser extent *O*-aroylaminopropioamidoximes with a β-benzimidazole substituent **7** and **8** had longer

**3. Search for new antitubercular drugs among the salts and bases of** *O***-aroylation products of β-(thiomorfolin-1-yl)- and**

A search for qualitatively new antitubercular drugs with the requirements of reducing the duration of treatment, eliminating of the rapid drug resistance development and toxic side effects of the existing antitubercular drugs, and reducing the cost of extremely expensive treatment of TB (DS, MDR, XDR) is being

1,5-Diphenylpyrroles have been identified as a class of compounds with high *in vitro* antitubercular activity. Replacing of the methylpiperazine substituent for thiomorpholine and replacing the chlorine atom in position 4 of the N-phenyl moiety with the fluorine atom, as well as varying the aromatic substituents at the C-2 atom of the pyrrole ring during the transition from *p*-CH3 (BM221) to *p*-CH3O (BM233) and to *p*-CH3S (BM579) in 1,5-(4-chlorophenyl)-2-methyl-3- (4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM212), leads to an increase in *in vitro* antitubercular activity on *M. tuberculosis* H37Rv strains [13, 14].

**β-(4-methylpiperazin-1-yl)propioamidoximes**

pounds. The anesthesia indices of **8** and **9** were almost the same as that for trimecaine and were slightly greater than those for lidocaine, novocaine, and kazcaine. The strength of the anesthesia induced by **4** and **7** was greater than that of novocaine, equal to that of kazcaine, and less than that of trimecaine and lidocaine. The anesthesia indices of **1**–**3** and **4** were less than those of the reference drugs. Compound **10** had a longer duration of conduction anesthesia than the other tested

*Amidoxime Derivatives with Local Anesthetic, Antitubercular, and Antidiabetic Activity*

compounds (including the reference drugs).

*DOI: http://dx.doi.org/10.5772/intechopen.90002*

trimecaine.

effect.

8.3 min) were comparable with that of novocaine.

durations of action than the reference drugs.

conducted in the world.

**31**

*\* Compared to trimecaine.*

*\*\*Compared with lidocaine.*

*\*\*\*In comparison with novocaine. \*\*\*\*Compared to cascaine.*

#### **Table 2.**

*Activity and duration of action of compounds 1–10 (1% concentration) for conduction anesthesia.*


#### **Table 3.**

*Activity and duration of action of compounds 1–10 (1% concentration) for terminal anesthesia.*

The experimental results indicated that all compounds **1**–**10** were effective to different degrees in infiltration anesthesia (**Table 1**). The most active compound was **10**, which induced the maximum deep anesthesia (anesthesia index 36.0) and exceeded statistically that of the reference drugs with the exception of lidocaine.

#### *Amidoxime Derivatives with Local Anesthetic, Antitubercular, and Antidiabetic Activity DOI: http://dx.doi.org/10.5772/intechopen.90002*

This compound also turned out to be more active than the other tested compounds. The anesthesia indices of **8** and **9** were almost the same as that for trimecaine and were slightly greater than those for lidocaine, novocaine, and kazcaine. The strength of the anesthesia induced by **4** and **7** was greater than that of novocaine, equal to that of kazcaine, and less than that of trimecaine and lidocaine. The anesthesia indices of **1**–**3** and **4** were less than those of the reference drugs. Compound **10** had a longer duration of conduction anesthesia than the other tested compounds (including the reference drugs).

Compounds **5** and **7**–**9** had longer durations of action than novocaine, shorter than trimecaine, and essentially the same as lidocaine and kazcaine. The duration of total anesthesia of **4** was longer than that of novocaine and slightly shorter than that of the other reference drugs. The durations of total anesthesia for **1** and **4** (10.0 and 8.3 min) were comparable with that of novocaine.

**Table 2** presents results from a study of conduction anesthesia by **1**–**10**.

Like in the preceding series of tests, **10** had the highest activity. Its anesthesia index was greater than those of trimecaine, lidocaine, and novocaine and equal to that of kazcaine. Compounds **1**–**5** and **7**–**9** were rather active. Their anesthesia indices were greater than those of trimecaine, novocaine, and lidocaine. However, they were less than that of kazcaine. Compound **6** was less active than the reference drugs. Like in the preceding series of tests, the durations of total anesthesia of the studied compounds were compared. **Table 2** shows that all compounds **1**–**10** had total anesthesia duration indices that were shorter than that of kazcaine although **3**, **4**, and **7**–**10** had durations of action longer than those of novocaine, lidocaine, and trimecaine.

Compounds **1**–**10** in terminal anesthesia were weaker and shorter acting than dicaine (**Table 3**). However, not one of these compounds exhibited an irritating effect.

Thus, it was shown that amidoxime derivatives **1**–**10** exhibited anesthetic effects that were greater than those of the reference drugs in conduction and infiltration anesthesia. The 1,2,4-oxadiazoles **9** and **10** and to a lesser extent *O*-aroylaminopropioamidoximes with a β-benzimidazole substituent **7** and **8** had longer durations of action than the reference drugs.

#### **3. Search for new antitubercular drugs among the salts and bases of** *O***-aroylation products of β-(thiomorfolin-1-yl)- and β-(4-methylpiperazin-1-yl)propioamidoximes**

A search for qualitatively new antitubercular drugs with the requirements of reducing the duration of treatment, eliminating of the rapid drug resistance development and toxic side effects of the existing antitubercular drugs, and reducing the cost of extremely expensive treatment of TB (DS, MDR, XDR) is being conducted in the world.

1,5-Diphenylpyrroles have been identified as a class of compounds with high *in vitro* antitubercular activity. Replacing of the methylpiperazine substituent for thiomorpholine and replacing the chlorine atom in position 4 of the N-phenyl moiety with the fluorine atom, as well as varying the aromatic substituents at the C-2 atom of the pyrrole ring during the transition from *p*-CH3 (BM221) to *p*-CH3O (BM233) and to *p*-CH3S (BM579) in 1,5-(4-chlorophenyl)-2-methyl-3- (4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM212), leads to an increase in *in vitro* antitubercular activity on *M. tuberculosis* H37Rv strains [13, 14].

The experimental results indicated that all compounds **1**–**10** were effective to different degrees in infiltration anesthesia (**Table 1**). The most active compound was **10**, which induced the maximum deep anesthesia (anesthesia index 36.0) and exceeded statistically that of the reference drugs with the exception of lidocaine.

*Activity and duration of action of compounds 1–10 (1% concentration) for terminal anesthesia.*

**Compound Anesthesia index**

*\**

**Table 2.**

**Table 3.**

**30**

*Compared to trimecaine. \*\*Compared with lidocaine. \*\*\*In comparison with novocaine. \*\*\*\*Compared to cascaine.*

**Compound Regnier index**

**(М m)**

**(М m)**

*Heterocycles - Synthesis and Biological Activities*

**Duration of complete anesthesia (М m), min**

 329.0 20.0\* 10.0 0.0\*\*\* 64.0 1.5\* 301.0 5.3\*\* 15.0 0.0\* 72.0 4.0\* 319.7 5.6\*\*\* 45.0 0.0\*\* 69.3 3.0\*\* 427.0 44.0\* 48.0 0.0\*\*\*\* 80.6 2.0\*\*\* 310.0 43.7\* 20.0 0.0\* 65.0 3.1\* 242.9 4.7\*\* 10.0 0.8\* 61.2 1.2\* 425.7 15.6\* 84.0 2.6\*\* 144.0 3.5\*\*\*\* 534.0 12.0\*\*\*\* 88.0 0.0\*\*\* 118.0 3.1\* 591.0 34.0\* 90.0 2.4\* 105.0 5.9\* 600.0 0.0\* 70.4 1.1\*\*\* 90.0 3.1\*\* Trimecaine 324.0 14.0 20.0 0.0 63.0 1.3 Lidocaine 366.8 94.8 10.0 0.0 68.0 2.8 Novocaine 310.0 43.7 10.0 0.0 60.0 0.0 Kazkain 600.0 0.0 208.9 7.3 280.0 0.0

*Activity and duration of action of compounds 1–10 (1% concentration) for conduction anesthesia.*

 85.6 5.0 0.0 14.4 1.5 242.5 16.4 0.0 33.1 1.6 186.3 9.7 0.0 28.0 2.4 150.6 16.2 0.0 27.5 1.9 281.6 18.5 0.0 38.0 1.9 13.0 0.0 0.0 0.0 103.0 10.5 0.0 22.0 0.9 373.4 37.3 0.0 43.1 4.0 601.5 32.7 0.0 62.0 2.3 430.0 14.4 0.0 48.75 2.1 Dikain 1300.0 0.0 65.0 0.0 120.0 0.0

**Duration of complete anesthesia (М m), min**

**Total duration of anesthesia (М m), min**

**Total duration of anesthesia (М m), min**

Taking into account the above examples, we synthesized compounds of the β-aminopropioamidoxime series containing in the β-position fragments of 1-methylpiperazine and thiomorpholine (**11**–**21**).

*In vitro* antitubercular screening of a series of *O*-aroyl-β-aminopropioamidoximes (**11**–**21**) on DS museum H37Rv and wild\* I MTB strains and two wild DR and MDR strains of MTB II and III on Shkolnikova liquid medium found that compounds **11**–**21** in varying degrees have antitubercular activity from >100 to 0.01 μg/ml (**Table 4**).

> Based on the high priority requirements of increasing the effectiveness and safety of treatment in the development of new antitubercular drugs, it can be argued that *O*-benzoyl-β-(thiomorpholin-1-yl)propioamidoxime and hydrochloride, iodomethylate of *O*-*p*-toluoyl-β-(4-methylpiperazine-1-yl)propioamidoxime,

*Bactericidal activity and average subcutaneous toxicity of O-aroyl-β-(thiomorpholin-1-yl)propioamidoximes (11–20) and double salt of O-p-toluoyl-(4-methylpiperazin-1-yl)propioamidoxime (21) on DS and DR*

*Wild strains of M. tuberculosis I, II, and III were isolated from the patients and typed in the RSE "National Scientific Center for Phthisiopulmonology of the Republic of Kazakhstan" of the Ministry of Health of the Republic of Kazakhstan: I, DS (drug-sensitive) to anti-TB drugs; II, DR (drug-resistant) to rifampicin; III, MDR (multidrug-*

The urgency of discovering effective medicines to treat diabetes and information about the antidiabetic activity of amidoxime derivatives [9–11] prompted us to test β-aminopropionamidoxime bases and pharmacologically acceptable salts of *O*aroyl-β-(morpholin-1-yl)propionamidoximes and 5-aryl-3-β-(piperidin-1-yl- and morpholin-1-yl)ethyl-1,2,4-oxadiazoles for *in vitro* inhibitory activity against the enzymes α-amylase and α-glucosidase, which determine the supply level of glucose

Herein, results from *in vitro* screening of new β-aminopropionamidoximes (**22**–**26**) for antidiabetic activity are now reported. The series of β-aminopropionamidoximes included bases and pharmacologically acceptable salts (hydrochloride, acetate, oxalate, citrate, and methyl iodide) of *O*-aroyl-β-(morpholin-1-yl) propionamidoximes **22**–**24** and 5-(*p*-, *m*-substituted phenyl)-3-(β-piperidin-1-yl-

are competitive because they are less toxic and more active than the basic

tuberculostatics used in practice: isoniazid and rifampicin.

**№ соmp. MBC on the** *M. tuberculosis* **strains, μg/ml**

*DOI: http://dx.doi.org/10.5772/intechopen.90002*

**H37Rv I II III LD50, mg/kg**

 >100 >100 100 100 — 100 100 100 100 — 100 100 100 100 — >100 >100 100 100 — 100 100 100 100 — 100 100 100 100 — >100 >100 >100 >100 —

*Amidoxime Derivatives with Local Anesthetic, Antitubercular, and Antidiabetic Activity*

 0.01 0.01 100 100 325.0 17.8 >20 >20 100 100 — 100 100 100 100 — 0.01 0.01 0.1 0.1 1750.0 35.6 Rifampicin 1 1 2 2 267.6 7.2 Isoniazid 0.1 0.1 1 1 62.5 12.8

**4. Inhibition of α-amylase and α-glucosidase by new**

**β-aminopropioamidoxime derivatives**

*resistant) to rifampicin, isoniazid, and ethambutol.*

*\**

**33**

**Table 4.**

*strains of M. tuberculosis.*

from the gastrointestinal tract into the blood pool.

and morpholin-1-yl)-1,2,4-oxadiazoles **25** and **26**.

Thus, on the DS strains of MTB *O*-benzoyl-β-(thiomorpholin-1-yl) propioamidoxime (**18**) and hydrochloride, iodomethylate of *O-p*-toluoyl-β- (1-methylpiperazin-1-yl)propioamidoxime (**21**) showed the highest activity at 0.01 μg/ml; compound **19** had an average antitubercular activity with MBC >20 μg/ml; the remaining compounds **11**–**17** and **20** had MBC from 100 to >100 μg/ml.

The highest activity in 0.1 μg/ml on DR and MDR strains of MTB II and III was shown by hydrochloride, iodomethylate of *O*-*p*-toluoyl-β-(1-methylpiperazin-1-yl) propioamidoxime (**21**) (**Table 4**).

The acute toxic effect of rifampicin, isoniazid, and compounds **18** and **21** (LD50) was determined on white mice of both sexes weighing 17–23 g when administered subcutaneously. The toxicity of rifampicin SV is 267.6 7.2 mg/kg; of isoniazid 62.5 12.8 mg/kg; and of compounds **18** and **21**, respectively, 325.0 17.8 and 1750.0 35.6 mg/kg.

Thus, hydrochloride, iodomethylate of *O-p*-toluoyl-β-(4-methylpiperazin-1-yl) propioamidoxime, is by 100 times more active against DS strains than rifampicin SV and by 10 times more active than isoniazid; it is by 20 times more active against DR strains than rifampicin SV and by 10 times more active than isoniazid. Hydrochloride, iodomethyl *O-p*-toluoyl-β-(4-methylpiperazin-1-yl)propioamidoxime, is less toxic than rifampicin SV by 6.5 times and by 28 times less toxic than isoniazid.

*O*-Benzoyl-β-(thiomorpholin-1-yl)propioamidoxime is by 100 times more active against DS strains than rifampicin SV and by 10 times more than isoniazid; it is less toxic than rifampicin SV by 1.2 times and by 5.2 times less toxic than isoniazid. These data are protected by the patents of the Republic of Kazakhstan [7, 8].


*Amidoxime Derivatives with Local Anesthetic, Antitubercular, and Antidiabetic Activity DOI: http://dx.doi.org/10.5772/intechopen.90002*

*\* Wild strains of M. tuberculosis I, II, and III were isolated from the patients and typed in the RSE "National Scientific Center for Phthisiopulmonology of the Republic of Kazakhstan" of the Ministry of Health of the Republic of Kazakhstan: I, DS (drug-sensitive) to anti-TB drugs; II, DR (drug-resistant) to rifampicin; III, MDR (multidrugresistant) to rifampicin, isoniazid, and ethambutol.*

#### **Table 4.**

Taking into account the above examples, we synthesized compounds of the

β-aminopropioamidoxime series containing in the β-position fragments of

*In vitro* antitubercular screening of a series of *O*-aroyl-β-aminopropioamidoximes (**11**–**21**) on DS museum H37Rv and wild\* I MTB strains and two wild DR and MDR strains of MTB II and III on Shkolnikova liquid medium found that compounds **11**–**21** in varying degrees have antitubercular activity from >100 to

Thus, on the DS strains of MTB *O*-benzoyl-β-(thiomorpholin-1-yl) propioamidoxime (**18**) and hydrochloride, iodomethylate of *O-p*-toluoyl-β- (1-methylpiperazin-1-yl)propioamidoxime (**21**) showed the highest activity at 0.01 μg/ml; compound **19** had an average antitubercular activity with MBC >20 μg/ml; the remaining compounds **11**–**17** and **20** had MBC from 100

The highest activity in 0.1 μg/ml on DR and MDR strains of MTB II and III was shown by hydrochloride, iodomethylate of *O*-*p*-toluoyl-β-(1-methylpiperazin-1-yl)

The acute toxic effect of rifampicin, isoniazid, and compounds **18** and **21** (LD50) was determined on white mice of both sexes weighing 17–23 g when administered subcutaneously. The toxicity of rifampicin SV is 267.6 7.2 mg/kg; of isoniazid 62.5 12.8 mg/kg; and of compounds **18** and **21**, respectively, 325.0 17.8 and

Thus, hydrochloride, iodomethylate of *O-p*-toluoyl-β-(4-methylpiperazin-1-yl) propioamidoxime, is by 100 times more active against DS strains than rifampicin SV and by 10 times more active than isoniazid; it is by 20 times more active against DR strains than rifampicin SV and by 10 times more active than isoniazid. Hydrochloride, iodomethyl *O-p*-toluoyl-β-(4-methylpiperazin-1-yl)propioamidoxime, is less toxic than rifampicin SV by 6.5 times and by 28 times less toxic than

*O*-Benzoyl-β-(thiomorpholin-1-yl)propioamidoxime is by 100 times more active against DS strains than rifampicin SV and by 10 times more than isoniazid; it is less toxic than rifampicin SV by 1.2 times and by 5.2 times less toxic than isoniazid. These data are protected by the patents of the Republic of Kazakhstan

1-methylpiperazine and thiomorpholine (**11**–**21**).

*Heterocycles - Synthesis and Biological Activities*

0.01 μg/ml (**Table 4**).

propioamidoxime (**21**) (**Table 4**).

to >100 μg/ml.

1750.0 35.6 mg/kg.

isoniazid.

[7, 8].

**32**

*Bactericidal activity and average subcutaneous toxicity of O-aroyl-β-(thiomorpholin-1-yl)propioamidoximes (11–20) and double salt of O-p-toluoyl-(4-methylpiperazin-1-yl)propioamidoxime (21) on DS and DR strains of M. tuberculosis.*

Based on the high priority requirements of increasing the effectiveness and safety of treatment in the development of new antitubercular drugs, it can be argued that *O*-benzoyl-β-(thiomorpholin-1-yl)propioamidoxime and hydrochloride, iodomethylate of *O*-*p*-toluoyl-β-(4-methylpiperazine-1-yl)propioamidoxime, are competitive because they are less toxic and more active than the basic tuberculostatics used in practice: isoniazid and rifampicin.

#### **4. Inhibition of α-amylase and α-glucosidase by new β-aminopropioamidoxime derivatives**

The urgency of discovering effective medicines to treat diabetes and information about the antidiabetic activity of amidoxime derivatives [9–11] prompted us to test β-aminopropionamidoxime bases and pharmacologically acceptable salts of *O*aroyl-β-(morpholin-1-yl)propionamidoximes and 5-aryl-3-β-(piperidin-1-yl- and morpholin-1-yl)ethyl-1,2,4-oxadiazoles for *in vitro* inhibitory activity against the enzymes α-amylase and α-glucosidase, which determine the supply level of glucose from the gastrointestinal tract into the blood pool.

Herein, results from *in vitro* screening of new β-aminopropionamidoximes (**22**–**26**) for antidiabetic activity are now reported. The series of β-aminopropionamidoximes included bases and pharmacologically acceptable salts (hydrochloride, acetate, oxalate, citrate, and methyl iodide) of *O*-aroyl-β-(morpholin-1-yl) propionamidoximes **22**–**24** and 5-(*p*-, *m*-substituted phenyl)-3-(β-piperidin-1-yland morpholin-1-yl)-1,2,4-oxadiazoles **25** and **26**.

Compounds **22**–**24a** and **b**, **25**, and **26** were described [12, 15, 16].

Compounds **24b**–**f** were derived from the base of *O*-*p*-toluoyl-β-(morpholin-1-yl)propionamidoxime **24a** and were prepared in one step by adding of equivalent amounts of organic acids (acetic, oxalic, citric) and methyl iodide in various solvents. Acetate **24c** was prepared by reacting **24a** with a twofold excess of glacial AcOH in refluxing in EtOH.

(morpholin-1-yl)propionamidoxime (**24e**, 37%); and 5-(*p*-toluoyl)-3-[(β-piperidin-

**Compound 22a 22b 23 24a 24b 24c 24d Acarbose**

*Amidoxime Derivatives with Local Anesthetic, Antitubercular, and Antidiabetic Activity*

**Compound 24e 24f 25a 25b 25c 26 Acarbose** Inhibition, % α-Amylase 37.0 3.4 — 43.0 3.0 51.0 9.1 — 48.0 5.9 71.0 2.7

α-Amylase — 48.0 5.8 35.0 0.6 32.5 0.22 27.0 5.5 25.6 0.26 — 71.0 2.7

<sup>α</sup>-Glucosidase — 78.1 4.41\*\* 67.2 0.82 68.7 1.81 67.2 1.79 61.7 2.26 75.0 1.32

*.*

23.0 0.84 45.1 1.99 22.8 0.09 34.7 1.36 27.4 0.15 — 75.0 1.32

The highest inhibitory activities against α-glucosidase were exhibited by O-*p*anisoyl-β-(morpholin-1-yl)propionamidoxime (**22a**, 78.7%); iodine methylate of O-*p*-toluoyl-β-(morpholin-1-yl)propionamidoxime (**24f**, 78.1%); and 5-(*m*chlorophenyl)-3-[(β-morpholin-1-yl)ethyl]-1,2,4-oxadiazole (**26**, 61.7%). Moderate inhibitory activity for α-glucosidase was manifested by O-*m*chlorobenzoyl-β-(morpholin-1-yl)propionamidoxime (**22b**, 23%) and its hydro-

The reference compound acarbose exhibited the standard inhibitory activity

In conclusion, it is noteworthy that bases and pharmacologically acceptable salts of *O*-aroyl-β-aminopropionamidoximes and 5-substituted phenyl-3-β-(piperidin-1 yl and morpholin-1-yl)ethyl-1,2,4-oxadiazoles (**22**–**26**) showed more pronounced inhibitory activity for α-glucosidase than for α-amylase. Both **22a** and **24f** had

A structure–activity relationship for two series of screening experiments found that, as a rule, 3,5-disubstituted 1,2,4-oxadiazoles exhibited greater inhibition of α-amylase and α-glucosidase than their chemical precursors, i.e., bases and pharmacologically acceptable salts of *O*-aroyl-β-aminopropionamidoximes.

Sincere gratitude is expressed to organic chemists and to the biological activity testers who provided support and understanding in resolving the practical issues addressed in this work: I.S. Zhumadildaeva, A.L. Ahelova, M.O. Orazbaeva, G.I.

The publication of this chapter was made possible thanks to the financial support for the basic research program on the topic "Physico-chemical fundamentals of creating inorganic, organic, polymer compounds, systems and materials with desired properties" and the award from the Ministry of Education and Science of

against α-amylase and α-glucosidase of 71.0 and 75.5%, respectively.

α-glucosidase activity comparable with that of the standard acarbose.

Gapparova, G.P. Baitursynova, A.B. Uzakova, G.T. Dyusembaeva, G.M. Pichkhadze, D.M. Kadyrova, G.S. Mukhamedzhanova, R.A. Agzamova, V.L. Bismilda, L.T. Chingisova, B.T. Toksanbaeva, A.E. Gulyaev, Z.T. Schulgau, and Sh.

the Republic of Kazakhstan No. 207 of 03/19/2018.

1-yl)ethyl]-1,2,4-oxadiazole (**25a**, 43%).

α-Glucosidase 78.7 0.9

*DOI: http://dx.doi.org/10.5772/intechopen.90002*

1\*\*

*Inhibitory activity of 22–26 for α-amylase and α-glucosidase, %\**

chloride (**23**, 45.1%).

Inhibition, %

*Activity absent (). \*\*p <sup>&</sup>gt; 0.05 vs. acarbose.*

*\**

**Table 5.**

**Acknowledgements**

D. Sergazu.

**35**

The *in vitro* activity of **22**–**26** for inhibition of α-amylase and α-glucosidase was tested using two series of experiments. **Table 5** presents the screening results using acarbose as the standard in both instances.

The greatest inhibitory activities (50%) for α-amylase were found for O-*m*chlorobenzoyl-β-(morpholin-1-yl)propionamidoxime (**22b**, 48%); 5-(*p*bromophenyl)-3-[(β-piperidin-1-yl)ethyl]-1,2,4-oxadiazole (**25b**, 51%); and 5-(*m*chlorophenyl)-3-[(β-morpholin-1-yl)ethyl]-1,2,4-oxadiazole (**26**, 48%). Moderate activity for α-amylase (from 27 to 43%) was found for O-*m*-chlorobenzoyl-β- (morpholin-1-yl)propionamidoxime hydrochloride (**23**, 35%); base *O-p*-toluoyl-β- (morpholin-1-yl)propionamidoxime (**24a**, 32.5%); citrate of *O-p*-toluoyl-β-

*Amidoxime Derivatives with Local Anesthetic, Antitubercular, and Antidiabetic Activity DOI: http://dx.doi.org/10.5772/intechopen.90002*


#### **Table 5.**

Compounds **22**–**24a** and **b**, **25**, and **26** were described [12, 15, 16].

AcOH in refluxing in EtOH.

*Heterocycles - Synthesis and Biological Activities*

acarbose as the standard in both instances.

**34**

Compounds **24b**–**f** were derived from the base of *O*-*p*-toluoyl-β-(morpholin-1-yl)propionamidoxime **24a** and were prepared in one step by adding of equivalent amounts of organic acids (acetic, oxalic, citric) and methyl iodide in various solvents. Acetate **24c** was prepared by reacting **24a** with a twofold excess of glacial

The *in vitro* activity of **22**–**26** for inhibition of α-amylase and α-glucosidase was tested using two series of experiments. **Table 5** presents the screening results using

The greatest inhibitory activities (50%) for α-amylase were found for O-*m*-

bromophenyl)-3-[(β-piperidin-1-yl)ethyl]-1,2,4-oxadiazole (**25b**, 51%); and 5-(*m*chlorophenyl)-3-[(β-morpholin-1-yl)ethyl]-1,2,4-oxadiazole (**26**, 48%). Moderate activity for α-amylase (from 27 to 43%) was found for O-*m*-chlorobenzoyl-β- (morpholin-1-yl)propionamidoxime hydrochloride (**23**, 35%); base *O-p*-toluoyl-β- (morpholin-1-yl)propionamidoxime (**24a**, 32.5%); citrate of *O-p*-toluoyl-β-

chlorobenzoyl-β-(morpholin-1-yl)propionamidoxime (**22b**, 48%); 5-(*p*-

*Inhibitory activity of 22–26 for α-amylase and α-glucosidase, %\* .*

(morpholin-1-yl)propionamidoxime (**24e**, 37%); and 5-(*p*-toluoyl)-3-[(β-piperidin-1-yl)ethyl]-1,2,4-oxadiazole (**25a**, 43%).

The highest inhibitory activities against α-glucosidase were exhibited by O-*p*anisoyl-β-(morpholin-1-yl)propionamidoxime (**22a**, 78.7%); iodine methylate of O-*p*-toluoyl-β-(morpholin-1-yl)propionamidoxime (**24f**, 78.1%); and 5-(*m*chlorophenyl)-3-[(β-morpholin-1-yl)ethyl]-1,2,4-oxadiazole (**26**, 61.7%).

Moderate inhibitory activity for α-glucosidase was manifested by O-*m*chlorobenzoyl-β-(morpholin-1-yl)propionamidoxime (**22b**, 23%) and its hydrochloride (**23**, 45.1%).

The reference compound acarbose exhibited the standard inhibitory activity against α-amylase and α-glucosidase of 71.0 and 75.5%, respectively.

In conclusion, it is noteworthy that bases and pharmacologically acceptable salts of *O*-aroyl-β-aminopropionamidoximes and 5-substituted phenyl-3-β-(piperidin-1 yl and morpholin-1-yl)ethyl-1,2,4-oxadiazoles (**22**–**26**) showed more pronounced inhibitory activity for α-glucosidase than for α-amylase. Both **22a** and **24f** had α-glucosidase activity comparable with that of the standard acarbose.

A structure–activity relationship for two series of screening experiments found that, as a rule, 3,5-disubstituted 1,2,4-oxadiazoles exhibited greater inhibition of α-amylase and α-glucosidase than their chemical precursors, i.e., bases and pharmacologically acceptable salts of *O*-aroyl-β-aminopropionamidoximes.

#### **Acknowledgements**

Sincere gratitude is expressed to organic chemists and to the biological activity testers who provided support and understanding in resolving the practical issues addressed in this work: I.S. Zhumadildaeva, A.L. Ahelova, M.O. Orazbaeva, G.I. Gapparova, G.P. Baitursynova, A.B. Uzakova, G.T. Dyusembaeva, G.M. Pichkhadze, D.M. Kadyrova, G.S. Mukhamedzhanova, R.A. Agzamova, V.L. Bismilda, L.T. Chingisova, B.T. Toksanbaeva, A.E. Gulyaev, Z.T. Schulgau, and Sh. D. Sergazu.

The publication of this chapter was made possible thanks to the financial support for the basic research program on the topic "Physico-chemical fundamentals of creating inorganic, organic, polymer compounds, systems and materials with desired properties" and the award from the Ministry of Education and Science of the Republic of Kazakhstan No. 207 of 03/19/2018.

*Heterocycles - Synthesis and Biological Activities*

**References**

s11094-006-0017-7

DJ, Litinas KE, Varella EA, Nicolaides DN. Mint: Recent

the biological applications of

10.2174/138161208784139675

arylacetylformamidoxime thiosemicarbazones and their tuberculostatic properties.

BF00763717

[3] Khalilova SF, Poplavskaya IA, Blonskaya LI, Blagodarnyi YA. Mint: N-

Pharmaceutical Chemistry Journal. 1986;**20**(12):846-848. DOI: 10.1007/

Pichkhadze GM, Mukhamedzhanova GS, et al. Mint: Local anesthetic activity of

Pharmaceutical Chemistry Journal. 2011;

[5] Fact Sheets WHO. The top 10 causes of death, 24 May 2018. [Internet]. 2018. Available from: https://www.who.int/ne ws-room/fact-sheets/detail/the-top-10-causes-of-death [Accessed: 4

[6] WHO. Implementing the end TB strategy: The essentials. 2015/2016. 130p. ISBN: 978924150993; WHO/ HTM/TB/2015.31. http://www.who.int/ tb/publications/2015/The\_Essentials\_ to\_End\_TB/en/ [Accessed: 4 September

[7] Kayukova LA, Orazbaeva MA, Bismilda VL. Highly active on sensitive strains of *M. tuberculosis* derivative of

[4] Kayukova LA, Praliev KD, Akhelova AL, Kemel'bekov US,

new amidoxime derivatives.

**45**(8):468-471. DOI: 10.1007/

s11094-011-0657-0

September 2019]

2019]

**37**

[1] Kayukova LA. Mint: Synthesis of 1,2,4-oxadiazoles (a review). Pharmaceutical Chemistry Journal. 2005;**39**(10):539-547. DOI: 10.1007/

*DOI: http://dx.doi.org/10.5772/intechopen.90002*

β-(thiomorpholin-1-yl)propioamidoxime. Pat. № 21544 RK. Bull. No. 12. (In Russian). 2011. Available from: https:// www.kazpatent.kz/ru; https://gosreestr. kazpatent.kz/ [Accessed: 5 September

propioamidoxime as a bactericidal agent

[9] International Diabetes Federation. IDF Diabetes Atlas. 8th ed. Brussels, Belgium: International Diabetes Federation; 2017. Available from: h ttps://diabetesatlas.org/resources/2017-a tlas.html [Accessed: 4 September 2019]

[10] Peter LN, Zoltan S, Kalman T, Laszlo T, Kalman T, Jozsef M, et al. Reducing overweight or obese. Pat. № 2443417 Russia. Patentee: N-GIN Laboratories Research, Inc. (US). 2012. Available from: http://www.freepatent. ru/images/patents/15/2443417/patent-2443417.pdf [Accessed: 4 September

[11] Zbigniew M, Katarzhina R, Kludkevich D, Daniel S, Krzysztof K,

Katarzyna M, et al. The novel

[12] Kayukova LA, Uzakova AB, Baitursynova GP, Dyusembaeva GT, Shul'gau ZT, Gulyaev AE, et al. Mint:

Inhibition of α-amylase and

derivatives of 3-phenylpropionic acid. Pat. № 2369602 Russia. Patentee: Adamed JV. Z OO. 2009. Available from: http://webcache.googleuserconte nt.com/search?q=cache:http: //bd.pate nt.su/2369000-2369999/pat/servl/servle t6a95.html [Accessed: 4 September

[8] Kayukova LA, Bismilda VL. Derivative of β-(piperazin-1-yl)

against sensitive, resistant and multidrug-resistant strains of *M. tuberculosis*. Pat. № 21543 RK. Bull. No. 12. (In Russian). 2011. Available from: https://www.kazpatent.kz/ru; https:// gosreestr.kazpatent.kz/ [Accessed: 5

September 2019]

2019]

2019]

2019]

*Amidoxime Derivatives with Local Anesthetic, Antitubercular, and Antidiabetic Activity*

[2] Fylaktakidou KC, Hajipavlou-Litina

developments in the chemistry and in

amidoximes. Current Pharmaceutical Design. 2008;**14**(10):1001-1047. DOI:

#### **Author details**

Lyudmila Kayukova\*, Umirzak Jussipbekov and Kaldybay Praliyev JSC "A. B. Bekturov Institute of Chemical Sciences", Аlmaty, Каzakhstan

\*Address all correspondence to: lkayukova@mail.ru

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Amidoxime Derivatives with Local Anesthetic, Antitubercular, and Antidiabetic Activity DOI: http://dx.doi.org/10.5772/intechopen.90002*

#### **References**

[1] Kayukova LA. Mint: Synthesis of 1,2,4-oxadiazoles (a review). Pharmaceutical Chemistry Journal. 2005;**39**(10):539-547. DOI: 10.1007/ s11094-006-0017-7

[2] Fylaktakidou KC, Hajipavlou-Litina DJ, Litinas KE, Varella EA, Nicolaides DN. Mint: Recent developments in the chemistry and in the biological applications of amidoximes. Current Pharmaceutical Design. 2008;**14**(10):1001-1047. DOI: 10.2174/138161208784139675

[3] Khalilova SF, Poplavskaya IA, Blonskaya LI, Blagodarnyi YA. Mint: Narylacetylformamidoxime thiosemicarbazones and their tuberculostatic properties. Pharmaceutical Chemistry Journal. 1986;**20**(12):846-848. DOI: 10.1007/ BF00763717

[4] Kayukova LA, Praliev KD, Akhelova AL, Kemel'bekov US, Pichkhadze GM, Mukhamedzhanova GS, et al. Mint: Local anesthetic activity of new amidoxime derivatives. Pharmaceutical Chemistry Journal. 2011; **45**(8):468-471. DOI: 10.1007/ s11094-011-0657-0

[5] Fact Sheets WHO. The top 10 causes of death, 24 May 2018. [Internet]. 2018. Available from: https://www.who.int/ne ws-room/fact-sheets/detail/the-top-10-causes-of-death [Accessed: 4 September 2019]

[6] WHO. Implementing the end TB strategy: The essentials. 2015/2016. 130p. ISBN: 978924150993; WHO/ HTM/TB/2015.31. http://www.who.int/ tb/publications/2015/The\_Essentials\_ to\_End\_TB/en/ [Accessed: 4 September 2019]

[7] Kayukova LA, Orazbaeva MA, Bismilda VL. Highly active on sensitive strains of *M. tuberculosis* derivative of

β-(thiomorpholin-1-yl)propioamidoxime. Pat. № 21544 RK. Bull. No. 12. (In Russian). 2011. Available from: https:// www.kazpatent.kz/ru; https://gosreestr. kazpatent.kz/ [Accessed: 5 September 2019]

[8] Kayukova LA, Bismilda VL. Derivative of β-(piperazin-1-yl) propioamidoxime as a bactericidal agent against sensitive, resistant and multidrug-resistant strains of *M. tuberculosis*. Pat. № 21543 RK. Bull. No. 12. (In Russian). 2011. Available from: https://www.kazpatent.kz/ru; https:// gosreestr.kazpatent.kz/ [Accessed: 5 September 2019]

[9] International Diabetes Federation. IDF Diabetes Atlas. 8th ed. Brussels, Belgium: International Diabetes Federation; 2017. Available from: h ttps://diabetesatlas.org/resources/2017-a tlas.html [Accessed: 4 September 2019]

[10] Peter LN, Zoltan S, Kalman T, Laszlo T, Kalman T, Jozsef M, et al. Reducing overweight or obese. Pat. № 2443417 Russia. Patentee: N-GIN Laboratories Research, Inc. (US). 2012. Available from: http://www.freepatent. ru/images/patents/15/2443417/patent-2443417.pdf [Accessed: 4 September 2019]

[11] Zbigniew M, Katarzhina R, Kludkevich D, Daniel S, Krzysztof K, Katarzyna M, et al. The novel derivatives of 3-phenylpropionic acid. Pat. № 2369602 Russia. Patentee: Adamed JV. Z OO. 2009. Available from: http://webcache.googleuserconte nt.com/search?q=cache:http: //bd.pate nt.su/2369000-2369999/pat/servl/servle t6a95.html [Accessed: 4 September 2019]

[12] Kayukova LA, Uzakova AB, Baitursynova GP, Dyusembaeva GT, Shul'gau ZT, Gulyaev AE, et al. Mint: Inhibition of α-amylase and

**Author details**

**36**

Lyudmila Kayukova\*, Umirzak Jussipbekov and Kaldybay Praliyev JSC "A. B. Bekturov Institute of Chemical Sciences", Аlmaty, Каzakhstan

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: lkayukova@mail.ru

provided the original work is properly cited.

*Heterocycles - Synthesis and Biological Activities*

α-glucosidase by new βaminopropionamidoxime derivatives. Pharmaceutical Chemistry Journal. 2019;**53**(2):129-133. DOI: 10.1007/ s11094-019-01966-5

[13] Poce G, Bates RH, Alfonso S, Cocozza M, Porretta GC, Ballell L, et al. Mint: Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute murine model of tuberculosis infection. PLoS ONE. 2013;**8**(2):e56980. DOI: 10.1371/journal.pone.0056980

[14] Biava M, Porretta GC, Poce G, Battilocchio C, Alfonso S, De Logu A, et al. Mint: Identification of a novel pyrrole derivative endowed with antimycobacterial activity and protection index comparable to that of the current antitubercular drugs streptomycin and rifampin. Bioorganic & Medicinal Chemistry. 2010;**18**(22): 8076-8084. DOI: 10.1016/j. bmc.2010.09.006

[15] Kayukova LA, Praliev KD, Zhumadil'daeva IS.Mint: Cyclization of *O*benzoyl-β-piperidinopropionamidoximes to form 5-phenyl-3-(β-piperidino)ethyl-1,2,4-oxadiazoles. Russian Chemical Bulletin. 2002;**51**(11):2100-2105. DOI: 10.1023/A:1021628430346

[16] Kayukova LA. Mint: Conditions for the heterocyclization of *O*-aroyl-βmorpholinopropioamidoximes to 5-aryl-3-(β-morpholino)ethyl-1,2,4 oxadiazoles. Chemistry of Heterocyclic Compounds. 2003;**39**(2):223-227. DOI: 10.1023/A:1023724626003

**39**

**Chapter 4**

**Abstract**

Recent Developments of

Derivatives as Potential

*Nerella Sridhar Goud, Pardeep Kumar* 

Anticancer Agents

*and Rose Dawn Bharath*

benzimidazole-based anticancer agents.

**1. Introduction to cancer**

Target-Based Benzimidazole

Cancer is one of the major life burdens and around 18.1 million new cancer cases and 9.6 million deaths have been estimated in 2018 globally. Recent reports of the World Health Organization (WHO) stated that about one in six death cases globally is mainly due to cancer. Hence, the development of efficacious drugs with novel mechanisms is necessary for various cancer types. The chemotherapy drug resistance and non-selectivity toward targets have turned the current cancer research on to the highly emerging selective targets for the development of potential anticancer agents. Benzimidazole is regarded as an essential pharmacophore of the cancer research because of wide anticancer potentials with versatile mechanisms to inhibit the tumor progression and also facile synthetic strategies for an easy synthesis of various benzimidazole derivatives. The selective anticancer potentials also depend on the substitution of the benzimidazole nucleus. Therefore, it would lead to providing a path for the development of novel target-specific and highly effective

**Keywords:** benzimidazole, cancer, specific targets, synthetic strategies

Cancer is one of the dreadful diseases in the world and mainly characterized by uncontrolled cell proliferation. Worldwide, one in six women and one in five men develop cancer during their lifetime, and one in eleven women and one in eight men die from the disease. Global data clearly show that nearly half of the new cases and more than half of the cancer deaths worldwide in 2018 are estimated to occur in Asian countries because the region has nearly 60% of the global population and it is estimated to have a rise of over 21.4 million new cases per year, with 13.2 million cancer deaths, by 2030. The top three cancer types *viz.* breast, lung, and colorectal are responsible for one-third of the cancer incidence and mortality burden worldwide [1, 2]. Behavioral risk factors such as tobacco usage and smoking; physical risk factors such as exposure to ionizing radiations and asbestos; and genetic predominant factors are the main contributors to cancer. Even though utmost care has been taken, the disease still causes the death of millions of people globally [3].

#### **Chapter 4**

α-glucosidase by new β-

s11094-019-01966-5

aminopropionamidoxime derivatives. Pharmaceutical Chemistry Journal. 2019;**53**(2):129-133. DOI: 10.1007/

*Heterocycles - Synthesis and Biological Activities*

[13] Poce G, Bates RH, Alfonso S, Cocozza M, Porretta GC, Ballell L, et al.

Mint: Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute murine model of tuberculosis infection. PLoS ONE. 2013;**8**(2):e56980. DOI: 10.1371/journal.pone.0056980

[14] Biava M, Porretta GC, Poce G, Battilocchio C, Alfonso S, De Logu A, et al. Mint: Identification of a novel pyrrole derivative endowed with antimycobacterial activity and

protection index comparable to that of the current antitubercular drugs streptomycin and rifampin. Bioorganic & Medicinal Chemistry. 2010;**18**(22):

Zhumadil'daeva IS.Mint: Cyclization of *O*benzoyl-β-piperidinopropionamidoximes to form 5-phenyl-3-(β-piperidino)ethyl-1,2,4-oxadiazoles. Russian Chemical Bulletin. 2002;**51**(11):2100-2105. DOI:

[16] Kayukova LA. Mint: Conditions for the heterocyclization of *O*-aroyl-βmorpholinopropioamidoximes to 5-aryl-3-(β-morpholino)ethyl-1,2,4 oxadiazoles. Chemistry of Heterocyclic Compounds. 2003;**39**(2):223-227. DOI:

8076-8084. DOI: 10.1016/j.

[15] Kayukova LA, Praliev KD,

10.1023/A:1021628430346

10.1023/A:1023724626003

**38**

bmc.2010.09.006

## Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents

*Nerella Sridhar Goud, Pardeep Kumar and Rose Dawn Bharath*

#### **Abstract**

Cancer is one of the major life burdens and around 18.1 million new cancer cases and 9.6 million deaths have been estimated in 2018 globally. Recent reports of the World Health Organization (WHO) stated that about one in six death cases globally is mainly due to cancer. Hence, the development of efficacious drugs with novel mechanisms is necessary for various cancer types. The chemotherapy drug resistance and non-selectivity toward targets have turned the current cancer research on to the highly emerging selective targets for the development of potential anticancer agents. Benzimidazole is regarded as an essential pharmacophore of the cancer research because of wide anticancer potentials with versatile mechanisms to inhibit the tumor progression and also facile synthetic strategies for an easy synthesis of various benzimidazole derivatives. The selective anticancer potentials also depend on the substitution of the benzimidazole nucleus. Therefore, it would lead to providing a path for the development of novel target-specific and highly effective benzimidazole-based anticancer agents.

**Keywords:** benzimidazole, cancer, specific targets, synthetic strategies

#### **1. Introduction to cancer**

Cancer is one of the dreadful diseases in the world and mainly characterized by uncontrolled cell proliferation. Worldwide, one in six women and one in five men develop cancer during their lifetime, and one in eleven women and one in eight men die from the disease. Global data clearly show that nearly half of the new cases and more than half of the cancer deaths worldwide in 2018 are estimated to occur in Asian countries because the region has nearly 60% of the global population and it is estimated to have a rise of over 21.4 million new cases per year, with 13.2 million cancer deaths, by 2030. The top three cancer types *viz.* breast, lung, and colorectal are responsible for one-third of the cancer incidence and mortality burden worldwide [1, 2]. Behavioral risk factors such as tobacco usage and smoking; physical risk factors such as exposure to ionizing radiations and asbestos; and genetic predominant factors are the main contributors to cancer. Even though utmost care has been taken, the disease still causes the death of millions of people globally [3].

Although scientific advances have focused on knowing the exact pathophysiology of the disease and tremendous efforts have been made on early diagnosis of cancer, the overall mortality rate has not subsided. Moreover, the cancer survival rate tends to be extremely low in some developing countries. This is due to the combination of both late-stage detection and limited access to time and qualitative treatment [4].

Radiotherapy, surgery, and chemotherapy are the usual cancer treatment strategies [5]. Among these, chemotherapy is considered as one of the efficient and first-line strategies in suppressing tumor prognosis and eradication. Most of the chemotherapeutic drugs target the key cellular mechanisms and inhibit the cell division and thereby prevent cancer cell multiplication. Current clinical anticancer drugs usually act on metabolically effective or fast replicating cells and show drawbacks such as poor selectivity between cancer cells and healthy cells [6]. Cancer cells generally disturb the cell signaling pathways and tissue morphogenesis for the neoplastic propagation of tumors. Therefore, targeting these cell pathways by cytotoxic agents has been a proven therapeutic approach to subside tumor growth and disease progression. Unfortunately, most of the cytotoxic drugs cause side effects due to the poor selectivity and specificity toward cancer cells. However, the higher toxic profiles and poor tolerance of the present chemotherapeutic drugs are major obstacles to the effective treatment of cancer [7, 8]. Therefore, it is highly pertinent to design and synthesize new anticancer agents with improved efficiency and reduced side effects to complement the present


**41**

**Figure 1.**

*Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents*

chemotherapeutic approaches. Identifying new drugs and drug combinations for cancer treatment is essential to combat this lethal disease. Hence, further research that emphasizes mainly on the development of efficient chemotherapeutic agents is an emerging area of research in the field of medicinal chemistry. The list of various

Benzimidazole heterocyclic nucleus can be termed as "Master Key" due to its overwhelming biological profile and synthetic applications in medicinal chemistry. It is among the top five most common five-membered aromatic nitrogen heterocycles in U.S. FDA-approved pharmaceutical drugs [10]. Benzimidazoles are structural isosteres of nucleobases due to the fused nitrogen nuclei and they readily interact with biomolecular targets and elicit many biological activities such as anticancer [11], anti-inflammatory [12], antiulcer [13], anti-hypertensive [14], and anthelmintic [15]. Akhtar et al. in his recent review described the therapeutic evolution of benzimidazole scaffolds during the last quinquennial period [16]. This nitrogen-containing heterocycle was present in a number of well-established clinical drugs with diverse therapeutic activities. For instance, drugs like rabeprazole (**1**) and omeprazole (**2**) are benzimidazole-containing drugs, act as proton pump inhibitors, and are, therefore, used in the treatment of stomach ulcers [17]. Albendazole (**3**) and thiabendazole (**4**) are anthelmintic drugs that act by the inhibition of tubulin polymerization and impair the uptake of glucose, eventually leading to the death of the parasites [18]. Nocodazole (**5**) is a well-recognized antineoplastic agent that mainly acts by tubulin polymerization inhibition. Candesartan (**6**) is a benzimidazole-based orally active potent angiotensin II receptor antagonist that is used for the treatment of hypertension [19]. Bendamustine (**7**) is nitrogen mustard which belongs to alkylating agents, a class of chemotherapeutic agent and used in the treatment of chronic lymphomas [20]. Dovotininb (**8**) is the orally active benzimidazole quinolinone compound with potential antineoplastic activity (**Figure 1**)*.* It strongly binds to the fibroblast growth receptor 3 (FGFR3) and

available chemotherapeutic agents has been shown in **Table 1** [9].

inhibits its phosphorylation and induces tumor cell death [21].

*Examples of drugs and other bioactive molecules containing benzimidazole motif.*

*DOI: http://dx.doi.org/10.5772/intechopen.90758*

**2. Introduction to Benzimidazole**

**Table 1.**

*Common anticancer drugs along with their mechanisms of action.*

*Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents DOI: http://dx.doi.org/10.5772/intechopen.90758*

chemotherapeutic approaches. Identifying new drugs and drug combinations for cancer treatment is essential to combat this lethal disease. Hence, further research that emphasizes mainly on the development of efficient chemotherapeutic agents is an emerging area of research in the field of medicinal chemistry. The list of various available chemotherapeutic agents has been shown in **Table 1** [9].

#### **2. Introduction to Benzimidazole**

*Heterocycles - Synthesis and Biological Activities*

**DNA interacting agents**

**Anti**-**metabolites**

**Antitubulin agents**

**Tyrosine kinase inhibitors**

**Angiogenesis/ Metastasis inhibitors**

**Alkylating agents Alkylation of DNA bases**

Intercalating agents Stacking between DNA base pairs

Topoisomerase inhibitors Topoisomerase I-camptothecins

Purine analogues Mercaptopurine Pyrimidine analogues 5-Fluorouracil DHFR inhibitors Methotrexate

Taxol Paclitaxel, Docetaxel

*Common anticancer drugs along with their mechanisms of action.*

Vinca alkaloids Vincristine, Vinblastine, Vinorelbine

Monoclonal antibody Trastuzumab: inhibits EGFR2, HER2

Monoclonal antibody Bevacizumab (Avastin): targets VEGF

Small molecule Imatinib (Gleevec): inhibits ABL, c-Kit kinase, PDGFR

Gefitinib (Iressa): inhibits EGFR

DNA cleaving agents Cause strand scission at the binding site-Bleomycin

Cross-linking agents Binding to DNA results in intra- and inter-strand cross-linking

**Procarbazine, dacarbazine, and temozolomide**

Anthracyclines-doxorubicin, epirubicin Mitoxantrone and actinomycin-D

Topoisomerase II-Anthracyclines, etoposide

Platinum complexes-carboplatin, cisplatin, oxaliplatin Nitrogen mustards-cyclophosphamide, ifosfamide

Although scientific advances have focused on knowing the exact pathophysiology of the disease and tremendous efforts have been made on early diagnosis of cancer, the overall mortality rate has not subsided. Moreover, the cancer survival rate tends to be extremely low in some developing countries. This is due to the combination of both late-stage detection and limited access to time and qualitative treatment [4]. Radiotherapy, surgery, and chemotherapy are the usual cancer treatment strategies [5]. Among these, chemotherapy is considered as one of the efficient and first-line strategies in suppressing tumor prognosis and eradication. Most of the chemotherapeutic drugs target the key cellular mechanisms and inhibit the cell division and thereby prevent cancer cell multiplication. Current clinical anticancer drugs usually act on metabolically effective or fast replicating cells and show drawbacks such as poor selectivity between cancer cells and healthy cells [6]. Cancer cells generally disturb the cell signaling pathways and tissue morphogenesis for the neoplastic propagation of tumors. Therefore, targeting these cell pathways by cytotoxic agents has been a proven therapeutic approach to subside tumor growth and disease progression. Unfortunately, most of the cytotoxic drugs cause side effects due to the poor selectivity and specificity toward cancer cells. However, the higher toxic profiles and poor tolerance of the present chemotherapeutic drugs are major obstacles to the effective treatment of cancer [7, 8]. Therefore, it is highly pertinent to design and synthesize new anticancer agents with improved efficiency and reduced side effects to complement the present

**40**

**Table 1.**

Benzimidazole heterocyclic nucleus can be termed as "Master Key" due to its overwhelming biological profile and synthetic applications in medicinal chemistry. It is among the top five most common five-membered aromatic nitrogen heterocycles in U.S. FDA-approved pharmaceutical drugs [10]. Benzimidazoles are structural isosteres of nucleobases due to the fused nitrogen nuclei and they readily interact with biomolecular targets and elicit many biological activities such as anticancer [11], anti-inflammatory [12], antiulcer [13], anti-hypertensive [14], and anthelmintic [15]. Akhtar et al. in his recent review described the therapeutic evolution of benzimidazole scaffolds during the last quinquennial period [16]. This nitrogen-containing heterocycle was present in a number of well-established clinical drugs with diverse therapeutic activities. For instance, drugs like rabeprazole (**1**) and omeprazole (**2**) are benzimidazole-containing drugs, act as proton pump inhibitors, and are, therefore, used in the treatment of stomach ulcers [17]. Albendazole (**3**) and thiabendazole (**4**) are anthelmintic drugs that act by the inhibition of tubulin polymerization and impair the uptake of glucose, eventually leading to the death of the parasites [18]. Nocodazole (**5**) is a well-recognized antineoplastic agent that mainly acts by tubulin polymerization inhibition. Candesartan (**6**) is a benzimidazole-based orally active potent angiotensin II receptor antagonist that is used for the treatment of hypertension [19]. Bendamustine (**7**) is nitrogen mustard which belongs to alkylating agents, a class of chemotherapeutic agent and used in the treatment of chronic lymphomas [20]. Dovotininb (**8**) is the orally active benzimidazole quinolinone compound with potential antineoplastic activity (**Figure 1**)*.* It strongly binds to the fibroblast growth receptor 3 (FGFR3) and inhibits its phosphorylation and induces tumor cell death [21].

**Figure 1.** *Examples of drugs and other bioactive molecules containing benzimidazole motif.*

In 1954, Tamm, Folkers, and co-workers first reported the synthesis and antiviral activities of halogenated benzimidazole nucleosides [22]. They found that 5,6-dichloro-1-β-D-ribofuranosyl benzimidazole (DRB) has multiple biological activities including activity against RNA and DNA viruses. DRB inhibits cellular RNA polymerase II, thus affecting the multiple cellular processes so that it is more cytotoxic than antiviral. Slayden et al. found that albendazole (**3**) and thiabendazole (**4**) known tubulin inhibitors interfered and delayed the *Mtb* cell division processes [23]. Later, Kumar et al. proposed that the benzimidazole core would be a novel FtsZ inhibitor, which will have activity against both drug-sensitive and drugresistant *Mtb* [24]. This molecular framework displays numerous biological properties and is usually present in various drug compositions. Benzimidazoles tethered to various bioactive pharmacophores have also displayed potent antitumor activities.

Benzimidazoles have revolutionized the drug discovery process by their diverse range of biological activities, which make this scaffold an indispensable anchor for the innovation of novel therapeutic agents. Thus, the therapeutic potential of the benzimidazole and related drugs has attracted researchers to design and synthesize more potent derivatives with a wide range of pharmacological activities. Owing to the immense synthetic value and extended bioactivities exhibited by benzimidazoles and their derivatives, efforts have been made from time to time to create libraries of these compounds.

#### **3. Target-based benzimidazole derivatives**

#### **3.1 Galectin-1 inhibitors**

Galectin-1 (Gal-1) is expressed in various normal and pathological conditions and has multiple functions with a wide range of biological activity. Gal-1, a human homodimeric lectin protein of 14KDa, is implicated in many signaling pathways, immune responses associated with cancer progression, neurological conditions, and immune disorders [25]. Gal-1 has a carbohydrate recognition domain (CRD), which is selective toward β-galactosides in the body. Inhibition of human Gal-1 has been regarded as one of the potential therapeutic approaches for the treatment of cancer, as it plays a major role in tumor development and metastasis by modulating various biological functions viz. angiogenesis, apoptosis, migration, and cell immune escape [26]. The overexpression of Gal-1 has been reported in many cancer types like the brain, breast, osteosarcoma, lung, prostate, melanoma, etc. [27]. Gal-1 can mediate neoplastic transformation by interacting with oncogenes, such as H-Ras and promote Ras-mediated signal transduction involving RAF1 and extracellular signal-regulated kinase (ERK). Gal-1 multivalently mediates tumor cell-ECM adhesion at the primary site by cross-linking cell surface glycoproteins, such as integrins, and glycosylated proteins in the ECM, such as laminin and fibronectin [28]. Hence, Gal-1 is regarded as a promising molecular target for the development of new therapeutic drugs for cancer.

Recently, a new series of 1-benzyl-1H-benzimidazole derivatives have been synthesized as Gal-1-mediated anticancer agents. The target compound (**9**) showed significant growth inhibition against breast cancer (MCF-7) cells with an IC50 value of 7.01 ± 0.20 μM. The target compound also showed good cytotoxicity in the range of 10.69–14.04 μM against colorectal cancer (HCT-116), breast cancer (MDA-MB-231), prostate cancer (DU-145), and lung cancer (A-549). In addition, *in-vitro* Gal-1 expression in cell supernatant of MCF-7 cells with compound (**9**) was measured in enzymatic GAL-1 ELISA studies and found to show dose-dependent reduction from 10 to 300 μM. The target compound showed Gal-1-mediated

**43**

**Figure 2.**

*Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents*

apoptosis, which was confirmed by morphological changes in MCF-7-treated cells like blebbing, cell wall deformation, and cell shrinkage, based on the apoptosis studies such as Acridine Orange/Ethidium Bromide (AO/EB) staining, DAPI nucleic acid staining, mitochondrial membrane potential, annexin V/propidium iodide dual staining assay, and dichlorofluorescein (DCF) fluorescence studies. In cell cycle analysis, the target compound selectively arrested MCF-7 cell growth at the G2/M phase and S phase. Further, the binding specificity of target compound toward Gal-1 was confirmed by surface plasmon resonance and fluorescence spectroscopy

in fluorescence spectroscopy studies, whereas the equilibrium constant (KD) value

ing of the target compound to Gal-1 was also confirmed by RP-HPLC studies and found to show 85.44% of binding to Gal-1. The molecular docking studies were also supported based on the strong amino acid interactions such as ARG48, TRP68, and

Tsung-Chieh Shih et al. reported a novel Gal-1 inhibitor named LLS2 (**10**), which was discovered through the One-Bead-Two-Compound library. The interaction of target gal-1 with LLS2 was confirmed by LC-MS/MS analytical and pull-down assay. The binding complex of LLS2 with Gal-1 selectively decreases membrane-specific H-Ras, and K-Ras pathways, lead to involve in the apoptosis process. The LLS2 exhibited a synergistic effect in combination with paclitaxel against many of the human cancer cell lines such as pancreatic cancer, ovarian cancer, and breast cancer cells *in vitro*. The combination of paclitaxel with LLS2 efficiently reduces the growth of ovarian cancer xenografts in athymic mice *in vivo*

The same group recently published a more potent Gal-1 inhibitor LLS3 (**11**), it impairs castration-resistant prostate cancer progression and invasion. LLS3 targets Gal-1 as an allosteric inhibitor, and reduces Gal-1 binding affinity toward its binding partners and also causes suppression of Akt, and AR signaling pathways. LLS3 showed *in vivo* efficacy in both androgen receptor-positive and negative xenograft models. In addition to potentiating the anticancer effect of docetaxel to cause suppression of tumors, it also efficiently suppresses the progression of prostate cancer

Tubulin is one of the members of a small family of globular proteins. Several isoforms are present out of which α- and β-tubulins are the most common members of tubulin. The cellular protein tubulin is an important protein for replication.

M was observed in surface plasmon resonance studies. The bind-

M<sup>−</sup><sup>1</sup>

was observed

studies and the specific binding constant value (Ka) of 1.2 × 104

*DOI: http://dx.doi.org/10.5772/intechopen.90758*

ASP125 with the target compound [29, 30].

of 5.76 × 10<sup>−</sup><sup>4</sup>

(**Figure 2**)*.*

cells *in vivo* [31, 32].

**3.2 Tubulin protein inhibitors**

*The novel benzimidazole derivatives as Gal-1 mediated anticancer agents.*

#### *Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents DOI: http://dx.doi.org/10.5772/intechopen.90758*

apoptosis, which was confirmed by morphological changes in MCF-7-treated cells like blebbing, cell wall deformation, and cell shrinkage, based on the apoptosis studies such as Acridine Orange/Ethidium Bromide (AO/EB) staining, DAPI nucleic acid staining, mitochondrial membrane potential, annexin V/propidium iodide dual staining assay, and dichlorofluorescein (DCF) fluorescence studies. In cell cycle analysis, the target compound selectively arrested MCF-7 cell growth at the G2/M phase and S phase. Further, the binding specificity of target compound toward Gal-1 was confirmed by surface plasmon resonance and fluorescence spectroscopy studies and the specific binding constant value (Ka) of 1.2 × 104 M<sup>−</sup><sup>1</sup> was observed in fluorescence spectroscopy studies, whereas the equilibrium constant (KD) value of 5.76 × 10<sup>−</sup><sup>4</sup> M was observed in surface plasmon resonance studies. The binding of the target compound to Gal-1 was also confirmed by RP-HPLC studies and found to show 85.44% of binding to Gal-1. The molecular docking studies were also supported based on the strong amino acid interactions such as ARG48, TRP68, and ASP125 with the target compound [29, 30].

Tsung-Chieh Shih et al. reported a novel Gal-1 inhibitor named LLS2 (**10**), which was discovered through the One-Bead-Two-Compound library. The interaction of target gal-1 with LLS2 was confirmed by LC-MS/MS analytical and pull-down assay. The binding complex of LLS2 with Gal-1 selectively decreases membrane-specific H-Ras, and K-Ras pathways, lead to involve in the apoptosis process. The LLS2 exhibited a synergistic effect in combination with paclitaxel against many of the human cancer cell lines such as pancreatic cancer, ovarian cancer, and breast cancer cells *in vitro*. The combination of paclitaxel with LLS2 efficiently reduces the growth of ovarian cancer xenografts in athymic mice *in vivo* (**Figure 2**)*.*

The same group recently published a more potent Gal-1 inhibitor LLS3 (**11**), it impairs castration-resistant prostate cancer progression and invasion. LLS3 targets Gal-1 as an allosteric inhibitor, and reduces Gal-1 binding affinity toward its binding partners and also causes suppression of Akt, and AR signaling pathways. LLS3 showed *in vivo* efficacy in both androgen receptor-positive and negative xenograft models. In addition to potentiating the anticancer effect of docetaxel to cause suppression of tumors, it also efficiently suppresses the progression of prostate cancer cells *in vivo* [31, 32].

#### **3.2 Tubulin protein inhibitors**

Tubulin is one of the members of a small family of globular proteins. Several isoforms are present out of which α- and β-tubulins are the most common members of tubulin. The cellular protein tubulin is an important protein for replication.

**Figure 2.** *The novel benzimidazole derivatives as Gal-1 mediated anticancer agents.*

*Heterocycles - Synthesis and Biological Activities*

libraries of these compounds.

**3.1 Galectin-1 inhibitors**

therapeutic drugs for cancer.

**3. Target-based benzimidazole derivatives**

In 1954, Tamm, Folkers, and co-workers first reported the synthesis and antiviral activities of halogenated benzimidazole nucleosides [22]. They found that 5,6-dichloro-1-β-D-ribofuranosyl benzimidazole (DRB) has multiple biological activities including activity against RNA and DNA viruses. DRB inhibits cellular RNA polymerase II, thus affecting the multiple cellular processes so that it is more cytotoxic than antiviral. Slayden et al. found that albendazole (**3**) and thiabendazole (**4**) known tubulin inhibitors interfered and delayed the *Mtb* cell division processes [23]. Later, Kumar et al. proposed that the benzimidazole core would be a novel FtsZ inhibitor, which will have activity against both drug-sensitive and drugresistant *Mtb* [24]. This molecular framework displays numerous biological properties and is usually present in various drug compositions. Benzimidazoles tethered to various bioactive pharmacophores have also displayed potent antitumor activities. Benzimidazoles have revolutionized the drug discovery process by their diverse range of biological activities, which make this scaffold an indispensable anchor for the innovation of novel therapeutic agents. Thus, the therapeutic potential of the benzimidazole and related drugs has attracted researchers to design and synthesize more potent derivatives with a wide range of pharmacological activities. Owing to the immense synthetic value and extended bioactivities exhibited by benzimidazoles and their derivatives, efforts have been made from time to time to create

Galectin-1 (Gal-1) is expressed in various normal and pathological conditions and has multiple functions with a wide range of biological activity. Gal-1, a human homodimeric lectin protein of 14KDa, is implicated in many signaling pathways, immune responses associated with cancer progression, neurological conditions, and immune disorders [25]. Gal-1 has a carbohydrate recognition domain (CRD), which is selective toward β-galactosides in the body. Inhibition of human Gal-1 has been regarded as one of the potential therapeutic approaches for the treatment of cancer, as it plays a major role in tumor development and metastasis by modulating various biological functions viz. angiogenesis, apoptosis, migration, and cell immune escape [26]. The overexpression of Gal-1 has been reported in many cancer types like the brain, breast, osteosarcoma, lung, prostate, melanoma, etc. [27]. Gal-1 can mediate neoplastic transformation by interacting with oncogenes, such as H-Ras and promote Ras-mediated signal transduction involving RAF1 and extracellular signal-regulated kinase (ERK). Gal-1 multivalently mediates tumor cell-ECM adhesion at the primary site by cross-linking cell surface glycoproteins, such as integrins, and glycosylated proteins in the ECM, such as laminin and fibronectin [28]. Hence, Gal-1 is regarded as a promising molecular target for the development of new

Recently, a new series of 1-benzyl-1H-benzimidazole derivatives have been synthesized as Gal-1-mediated anticancer agents. The target compound (**9**) showed significant growth inhibition against breast cancer (MCF-7) cells with an IC50 value of 7.01 ± 0.20 μM. The target compound also showed good cytotoxicity in the range of 10.69–14.04 μM against colorectal cancer (HCT-116), breast cancer (MDA-MB-231), prostate cancer (DU-145), and lung cancer (A-549). In addition, *in-vitro* Gal-1 expression in cell supernatant of MCF-7 cells with compound (**9**) was measured in enzymatic GAL-1 ELISA studies and found to show dose-dependent reduction from 10 to 300 μM. The target compound showed Gal-1-mediated

**42**

Microtubules are hallowing filaments and composed of head and tail polar fashion arrangements of α- and β-tubulins as the constituent subunits. Microtubules contain 13 active protofilaments aligned parallel with the whole axis of the microtubule cylinder. This may provide continuous transport of cellular materials by motor proteins (dynein and kinesin) over distant places. Microtubules also form an integral part of the cytoskeleton and are responsible for the maintenance of cell shape, and motility and intracellular transport of the vesicles, mitochondria, and other components [33, 34]. Moreover, cell division involves the duplication of DNA and the segregation of the replicated chromosomes into two daughter nuclei. The segregation of these chromosomes is mitotic phase is brought by the microtubules. In the formation of the microtubule, the plus (+) end is terminated by β-tubulin whereas the minus (−) end is terminated by α-tubulin. They are always either in a state of polymerization or depolymerization. Microtubules have the ability to shorten or lengthen in a scholastic fashion through loss or addition of α/β-tubulin heterodimers from ends of microtubules. This property is referred to as "dynamic instability" [35, 36]. Microtubules are blessed with a property to grow continuously as long as the free tubulin amount is above a critical level. The critical concentration at the minus end is somewhat higher than at the plus end and the minus end tends to stop growing first. Even above the critical tubulin concentration, its end may suddenly stop growing and begin to shrink. The change from growth to shrinkage has been termed as "catastrophe." After some time, a shrinking microtubule end may "pause" and/or begin to grow again; the latter process is known as "rescue." During mitotic cell division, the chromosomes are segregated by the mitotic spindle, which is formed from tubulin microtubules. Therefore, tubulin dynamics have a distinct role in cell division. Some of the drugs affect the microtubulin dynamics and thus cause either polymerization or depolymerization and thereby alter cellular replication. So at the mechanistic level, tubulin is one of the most attractive and challenging approaches for designing new anticancer compounds.

Zhang et al. have synthesized a series of 1,2-diarylbenzimidazole derivatives and reported as potential anticancer agents. Among all, the target molecule (**12**) has been found to show significant cytotoxicity against human cancer cells such as A549, HepG2, HeLa, and MCF-7 cells in the range of GI50 = 0.71–2.41 μM and also found to show normal cytotoxicity toward normal cells. The apoptosis process by the target compound was confirmed by morphological changes on HepG2 and HeLa-treated cells like cell wall deformation, blebbing, and cell shrinkage, based on apoptosis studies such as mitochondrial membrane potential, annexin V/propidium iodide dual staining assay, and dichlorofluorescein (DCF) fluorescence studies. In cell cycle analysis, the target compound selectively arrested tumor growth at the G2/M phase. Further, the target compound showed significant inhibition of microtubule polymerization with an IC50 value of 8.47 μM. The molecular docking simulation studies were performed to confirm the binding of the target compound with microtubule protein and found that the target compound has made strong interactions with protein [37].

Miao et al. reported a novel series of 2-aryl-benzimidazole-based dehydroabietic acid derivatives as potential cytotoxic agents via targeting tubulin polymerization. The synthesized molecules were characterized by elemental and analytical techniques. The target compound (**13**) showed significant growth inhibition against hepatocarcinoma cancer (SMMC-7721) cells with an IC50 value of 0.08 ± 0.01 μM. The target compound also showed good cytotoxicity in the range of 0.04–0.07 μM against breast cancer (MDA-MB-231), cervical cancer (HeLa), and colon cancer (CT-26). The apoptosis studies such as ROS levels measurements, loss of mitochondrial membrane potential, and cell cycle analysis were performed to confirm the induction of apoptosis in hepatocarcinoma cancer (SMMC-7721)

**45**

**Figure 3.**

*Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents*

cells. In cell cycle analysis, the target compound selectively arrested tumor growth at the G2/M phase. Further, the target compound showed significant inhibition of microtubule polymerization with an IC50 of 5 μM. The molecular docking studies supported the selectivity of the target compound to tubulin protein based on strong

Wang et al. reported a new series of benzimidazole containing benzsulfamide-

The human carbonic anhydrases (hCAs) are an α-family of carbonic anhydrases class and exist in 16 different isoforms [41]. Based on their location in the body,

*The target benzimidazole derivatives as selective anticancer agents via targeting tubulin polymerization.*

electronic interactions between the target compounds and tubulin [38].

pyrazole ring derivatives as potential tubulin polymerization inhibitors. The target compound (**14**) showed significant growth inhibition against lung cancer (A549) cells with an IC50 value of 0.15 ± 0.05 μM and also showed good growth inhibition against Hela, HepG2, and MCF-7 cell lines in the range of 0.17–0.33 μM concentration. Further, the target compound showed significant inhibition of microtubule polymerization with an IC50 value of 1.52 μM. In cell cycle analysis, the target compound selectively arrested A549 cell growth at the G2/M phase. The target compound showed A549 cell apoptosis based on the studies of annexin V/ propidium iodide dual staining assay and cell cycle analysis. The molecular docking studies were also supported based on the strong amino acid interactions such as LYS 352, LYS 254, ASN 258, and CYS 241 with the target compound [39] (**Figure 3**). Baig et al. have reported a series of imidazo [2,1-b] thiazole-benzimidazole derivatives as antiproliferative agents via tubulin polymerization inhibition. The target molecule (**15**) has shown significant cytotoxicity against human lung (A549) cancer with an IC50 value of 1.08 μM. It also showed good cytotoxicity toward DU-145 (prostate), MCF-7 (breast cancer), A549 (lung cancer), and HeLa (cervical cancer) in the range of 1.65–7.55 μM. In cell cycle analysis, the target compound selectively arrested A549 cell growth at the G2/M phase. The target compound showed apoptosis, which was confirmed by morphological changes in A549-treated cells like blebbing, cell wall deformation, and cell shrinkage, based on the apoptosis studies such as Hoechst staining, mitochondrial membrane potential, annexin V/ propidium iodide dual staining assay. Further, the target compound exhibits a significant inhibition of microtubule assembly with an IC50 of 1.68 μM. The computational studies revealed that the target compound can easily be occupied in the

*DOI: http://dx.doi.org/10.5772/intechopen.90758*

colchicine binding site of the protein [40].

**3.3 Carbonic anhydrase inhibitors**

#### *Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents DOI: http://dx.doi.org/10.5772/intechopen.90758*

cells. In cell cycle analysis, the target compound selectively arrested tumor growth at the G2/M phase. Further, the target compound showed significant inhibition of microtubule polymerization with an IC50 of 5 μM. The molecular docking studies supported the selectivity of the target compound to tubulin protein based on strong electronic interactions between the target compounds and tubulin [38].

Wang et al. reported a new series of benzimidazole containing benzsulfamidepyrazole ring derivatives as potential tubulin polymerization inhibitors. The target compound (**14**) showed significant growth inhibition against lung cancer (A549) cells with an IC50 value of 0.15 ± 0.05 μM and also showed good growth inhibition against Hela, HepG2, and MCF-7 cell lines in the range of 0.17–0.33 μM concentration. Further, the target compound showed significant inhibition of microtubule polymerization with an IC50 value of 1.52 μM. In cell cycle analysis, the target compound selectively arrested A549 cell growth at the G2/M phase. The target compound showed A549 cell apoptosis based on the studies of annexin V/ propidium iodide dual staining assay and cell cycle analysis. The molecular docking studies were also supported based on the strong amino acid interactions such as LYS 352, LYS 254, ASN 258, and CYS 241 with the target compound [39] (**Figure 3**).

Baig et al. have reported a series of imidazo [2,1-b] thiazole-benzimidazole derivatives as antiproliferative agents via tubulin polymerization inhibition. The target molecule (**15**) has shown significant cytotoxicity against human lung (A549) cancer with an IC50 value of 1.08 μM. It also showed good cytotoxicity toward DU-145 (prostate), MCF-7 (breast cancer), A549 (lung cancer), and HeLa (cervical cancer) in the range of 1.65–7.55 μM. In cell cycle analysis, the target compound selectively arrested A549 cell growth at the G2/M phase. The target compound showed apoptosis, which was confirmed by morphological changes in A549-treated cells like blebbing, cell wall deformation, and cell shrinkage, based on the apoptosis studies such as Hoechst staining, mitochondrial membrane potential, annexin V/ propidium iodide dual staining assay. Further, the target compound exhibits a significant inhibition of microtubule assembly with an IC50 of 1.68 μM. The computational studies revealed that the target compound can easily be occupied in the colchicine binding site of the protein [40].

#### **3.3 Carbonic anhydrase inhibitors**

The human carbonic anhydrases (hCAs) are an α-family of carbonic anhydrases class and exist in 16 different isoforms [41]. Based on their location in the body,

*Heterocycles - Synthesis and Biological Activities*

approaches for designing new anticancer compounds.

interactions with protein [37].

Zhang et al. have synthesized a series of 1,2-diarylbenzimidazole derivatives and reported as potential anticancer agents. Among all, the target molecule (**12**) has been found to show significant cytotoxicity against human cancer cells such as A549, HepG2, HeLa, and MCF-7 cells in the range of GI50 = 0.71–2.41 μM and also found to show normal cytotoxicity toward normal cells. The apoptosis process by the target compound was confirmed by morphological changes on HepG2 and HeLa-treated cells like cell wall deformation, blebbing, and cell shrinkage, based on apoptosis studies such as mitochondrial membrane potential, annexin V/propidium iodide dual staining assay, and dichlorofluorescein (DCF) fluorescence studies. In cell cycle analysis, the target compound selectively arrested tumor growth at the G2/M phase. Further, the target compound showed significant inhibition of microtubule polymerization with an IC50 value of 8.47 μM. The molecular docking simulation studies were performed to confirm the binding of the target compound with microtubule protein and found that the target compound has made strong

Miao et al. reported a novel series of 2-aryl-benzimidazole-based dehydroabietic

acid derivatives as potential cytotoxic agents via targeting tubulin polymerization. The synthesized molecules were characterized by elemental and analytical techniques. The target compound (**13**) showed significant growth inhibition against hepatocarcinoma cancer (SMMC-7721) cells with an IC50 value of

0.08 ± 0.01 μM. The target compound also showed good cytotoxicity in the range of 0.04–0.07 μM against breast cancer (MDA-MB-231), cervical cancer (HeLa), and colon cancer (CT-26). The apoptosis studies such as ROS levels measurements, loss of mitochondrial membrane potential, and cell cycle analysis were performed to confirm the induction of apoptosis in hepatocarcinoma cancer (SMMC-7721)

Microtubules are hallowing filaments and composed of head and tail polar fashion arrangements of α- and β-tubulins as the constituent subunits. Microtubules contain 13 active protofilaments aligned parallel with the whole axis of the microtubule cylinder. This may provide continuous transport of cellular materials by motor proteins (dynein and kinesin) over distant places. Microtubules also form an integral part of the cytoskeleton and are responsible for the maintenance of cell shape, and motility and intracellular transport of the vesicles, mitochondria, and other components [33, 34]. Moreover, cell division involves the duplication of DNA and the segregation of the replicated chromosomes into two daughter nuclei. The segregation of these chromosomes is mitotic phase is brought by the microtubules. In the formation of the microtubule, the plus (+) end is terminated by β-tubulin whereas the minus (−) end is terminated by α-tubulin. They are always either in a state of polymerization or depolymerization. Microtubules have the ability to shorten or lengthen in a scholastic fashion through loss or addition of α/β-tubulin heterodimers from ends of microtubules. This property is referred to as "dynamic instability" [35, 36]. Microtubules are blessed with a property to grow continuously as long as the free tubulin amount is above a critical level. The critical concentration at the minus end is somewhat higher than at the plus end and the minus end tends to stop growing first. Even above the critical tubulin concentration, its end may suddenly stop growing and begin to shrink. The change from growth to shrinkage has been termed as "catastrophe." After some time, a shrinking microtubule end may "pause" and/or begin to grow again; the latter process is known as "rescue." During mitotic cell division, the chromosomes are segregated by the mitotic spindle, which is formed from tubulin microtubules. Therefore, tubulin dynamics have a distinct role in cell division. Some of the drugs affect the microtubulin dynamics and thus cause either polymerization or depolymerization and thereby alter cellular replication. So at the mechanistic level, tubulin is one of the most attractive and challenging

**44**

they are classified into cytosolic hCAs such as CA I, CA II, CA III, CA VII, and CA XIII; transmembrane hCAs such as CA IV, CA IX, CA XII, CA XIV, and CA XV; mitochondrial-bound hCAs such as CA Va and Vb; secretory hCAs such as CA VI; and catalytically inactive isoforms like CA VIII, CA X, and CA XI, which are considered as CA-related proteins (CARPs) [42]. Among all, the hCA isoforms IX and XII are overexpressed in many of cancer types as these are tumor-associated transmembrane bound enzymes, mainly hypoxic tumors, which are regarded as emerging potential targets for various tumor types [43]. The overexpression of hCA isoforms IX and XII further contributes to the tumor progression, angiogenesis, metastasis, and proliferation of a variety of tumor cells [44]. In order to exhibit potential cytotoxicity without adverse effects, an anticancer agent should selectively inhibit tumor-associated hCAs IX and XII over other hCAs. Therefore, current cancer research focuses on the development of various heterocycles that selectively target tumor-linked hCA isoforms IX and XII for effective treatment strategies in cancer therapy [45]. Another hCA isoform II is also found to overexpress in some forms of cancer and other conditions like edema, glaucoma, and epilepsy.

Recently, a new series of 2-substituted-benzimidazole-6-sulfonamides have been reported as anticancer potentials by testing against four physiologically relevant hCAs such as CA I, CA II, CA IX, and CA XII. The analysis of hCA inhibition results showed that the new series of benzimidazole-based sulfonamide derivatives exhibited selective inhibition toward tumor-associated isoforms such as CA IX and CA XII. The target molecule (**16**) of this series had shown a promising inhibition at low μM range against hCA IX and XII isoform, with an inhibitory constant (Ki) value of 2.2 and 22.3 μM. Another potent compound **(17)** also exhibited good inhibition at low μM range against hCA IX and XII, with an inhibitory constant (Ki) value of 5.9 and 7.9 μM respectively. Hence, it is concluded that these benzimidazole derivatives might be potential anticancer agents exhibiting a novel mechanism through inhibition of hCA isoforms IX and XII [46]. Asta Zubriene et al. have reported a series of novel benzenesulfonamides with benzimidazole derivatives as selective human carbonic anhydrase I, II, VII, XII, and XIII inhibitors. The target molecules were synthesized from the precursor benzimidazole derivative with different phenacyl bromides. The target molecules **(18, 19)** were evaluated against five physiological relevant hCA isoforms (hCA, EC 4.2.1.1) CA I, CA II, CA VII, CA XII, and CA XIII. The target compound exhibited a promising inhibitory action at a lower nanomolar level against selected hCAs with an inhibitory constant (Ki) value range of 1.67–66.7 μM. Another target molecule has shown significant inhibition at lower nanomolar level against selected hCAs with an inhibitory constant (Ki) value range of 2.86–62.5 μM [47] (**Figure 4**).

#### **3.4 Epidermal growth factor receptor (EGFR) inhibitors**

The Epidermal Growth Factor Receptor is a subfamily transmembrane glycoprotein (ErbB-1) of ErbB class of tyrosine kinase receptors and, other subfamilies include HER2/neu (ErbB-2), Her 3 (ErbB-3) and, Her 4 (ErbB-4) [48]. The internal ligands like EGF and TGF facilitate the growth-promoting signal to cells by interacting with EGFR receptors and regulate epithelial tissue development and homeostasis [49, 50]. In cancer, especially epithelial malignancies, due to overproduction of EGFR ligands in the tumor micro environment causes continual activation (or) mutations of EGFR receptors, result in enhances epithelial tumor growth, metastasis and invasion [51, 52].

In a recent study, a new series of benzimidazole-based triazole and thiadiazole derivatives were synthesized and evaluated as selective EGFR inhibitors. The singlecrystal X-ray crystallographic analysis has been performed to confirm the molecular

**47**

**Figure 4.**

*Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents*

structure of the target compound. The synthesized compounds were evaluated for their EGFR kinase inhibitory potencies with erlotinib as the reference standard and, most of the compounds showed promising activities. The cell inhibition studies were also performed and the target compound (**20**) exhibited a significant inhibition and exhibited EGFR kinase inhibitory activity (over ≥30%) against MCF7 cells. The molecular docking studies indicated that the target compound showed two-hydrogen bonding interactions with residues of LYS721 and THR830 at the binding site of EGFR tyrosine kinase [53]. Akhtar et al. reported the benzimidazole-oxadiazole hybrids as selective EGFR and erbB2 receptor inhibitors. In *in vitro* cell inhibition studies, the target compound (**21**) exhibited a significant inhibition with an IC50 of 5.0 μM against breast cancer (MCF-7) cells. The target compound was found to show significant inhibition of EGFR and erbB2 receptor at 0.081 and 0.098 μM respectively. Most of the synthesized compounds exhibited a good cytotoxic activity against selected human cancer cell lines. In cell cycle analysis, the target compound selectively arrested MCF-7 cell growth at the G2/M phase. The computational and 3D-QSAR studies indicated that the target compound exhibited strong interactions with Asp831, Met769, and Thr830 of the EGFR enzyme [54]. Akhtar et al. have synthesized benzimidazole-based pyrazole derivatives through a one-pot multicomponent reaction and evaluated them for their potential anticancer activities. The synthesized compounds were screened against selected human cancer cell lines such as MCF-7, MDA-MB231, A549, HepG2, and HaCaT. The evaluation of EGFR inhibitory activities was performed for all the synthesized compounds. The target compound (**22**) exhibited promising cytotoxicity against the lung (A549) cancer cell lines with an IC50 value of 2.2 mM and the EGFR receptor inhibition value with an IC50 of 0.97 mM. In cell cycle analysis, the target compound selectively arrested A549 cell growth at the G2/M phase. In addition, it suppressed the growth of lung cancer cells by inducing apoptosis. In molecular docking studies, the target compound showed strong electronic interactions with Met769, Thr830, Lys721, and Phe699 of the active pocket of the EGFR receptor [55]. Yuan et al. have synthesized a library of 6-amide-2-aryl benzoxazole/benzimidazole derivatives and evaluated them for their selective inhibitory activities against VEGFR-2. The library of compounds exhibited selective anticancer activity against the liver hepatocellular carcinoma (HepG2), and human umbilical vein endothelial cells (HUVECs) over the lung cancer (A549) and breast (MDA-MB-231) cancer

*The benzimidazole derivatives as human carbonic anhydrase enzyme mediated anticancer agents.*

*DOI: http://dx.doi.org/10.5772/intechopen.90758*

*Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents DOI: http://dx.doi.org/10.5772/intechopen.90758*

#### **Figure 4.**

*Heterocycles - Synthesis and Biological Activities*

they are classified into cytosolic hCAs such as CA I, CA II, CA III, CA VII, and CA XIII; transmembrane hCAs such as CA IV, CA IX, CA XII, CA XIV, and CA XV; mitochondrial-bound hCAs such as CA Va and Vb; secretory hCAs such as CA VI; and catalytically inactive isoforms like CA VIII, CA X, and CA XI, which are considered as CA-related proteins (CARPs) [42]. Among all, the hCA isoforms IX and XII are overexpressed in many of cancer types as these are tumor-associated transmembrane bound enzymes, mainly hypoxic tumors, which are regarded as emerging potential targets for various tumor types [43]. The overexpression of hCA isoforms IX and XII further contributes to the tumor progression, angiogenesis, metastasis, and proliferation of a variety of tumor cells [44]. In order to exhibit potential cytotoxicity without adverse effects, an anticancer agent should selectively inhibit tumor-associated hCAs IX and XII over other hCAs. Therefore, current cancer research focuses on the development of various heterocycles that selectively target tumor-linked hCA isoforms IX and XII for effective treatment strategies in cancer therapy [45]. Another hCA isoform II is also found to overexpress in some forms of

Recently, a new series of 2-substituted-benzimidazole-6-sulfonamides have been

reported as anticancer potentials by testing against four physiologically relevant hCAs such as CA I, CA II, CA IX, and CA XII. The analysis of hCA inhibition results showed that the new series of benzimidazole-based sulfonamide derivatives exhibited selective inhibition toward tumor-associated isoforms such as CA IX and CA XII. The target molecule (**16**) of this series had shown a promising inhibition at low μM range against hCA IX and XII isoform, with an inhibitory constant (Ki) value of 2.2 and 22.3 μM. Another potent compound **(17)** also exhibited good inhibition at low μM range against hCA IX and XII, with an inhibitory constant (Ki) value of 5.9 and 7.9 μM respectively. Hence, it is concluded that these benzimidazole derivatives might be potential anticancer agents exhibiting a novel mechanism through inhibition of hCA isoforms IX and XII [46]. Asta Zubriene et al. have reported a series of novel benzenesulfonamides with benzimidazole derivatives as selective human carbonic anhydrase I, II, VII, XII, and XIII inhibitors. The target molecules were synthesized from the precursor benzimidazole derivative with different phenacyl bromides. The target molecules **(18, 19)** were evaluated against five physiological relevant hCA isoforms (hCA, EC 4.2.1.1) CA I, CA II, CA VII, CA XII, and CA XIII. The target compound exhibited a promising inhibitory action at a lower nanomolar level against selected hCAs with an inhibitory constant (Ki) value range of 1.67–66.7 μM. Another target molecule has shown significant inhibition at lower nanomolar level against selected hCAs with an inhibitory constant (Ki) value range

cancer and other conditions like edema, glaucoma, and epilepsy.

**46**

of 2.86–62.5 μM [47] (**Figure 4**).

metastasis and invasion [51, 52].

**3.4 Epidermal growth factor receptor (EGFR) inhibitors**

The Epidermal Growth Factor Receptor is a subfamily transmembrane glycoprotein (ErbB-1) of ErbB class of tyrosine kinase receptors and, other subfamilies include HER2/neu (ErbB-2), Her 3 (ErbB-3) and, Her 4 (ErbB-4) [48]. The internal ligands like EGF and TGF facilitate the growth-promoting signal to cells by interacting with EGFR receptors and regulate epithelial tissue development and homeostasis [49, 50]. In cancer, especially epithelial malignancies, due to overproduction of EGFR ligands in the tumor micro environment causes continual activation (or) mutations of EGFR receptors, result in enhances epithelial tumor growth,

In a recent study, a new series of benzimidazole-based triazole and thiadiazole derivatives were synthesized and evaluated as selective EGFR inhibitors. The singlecrystal X-ray crystallographic analysis has been performed to confirm the molecular

*The benzimidazole derivatives as human carbonic anhydrase enzyme mediated anticancer agents.*

structure of the target compound. The synthesized compounds were evaluated for their EGFR kinase inhibitory potencies with erlotinib as the reference standard and, most of the compounds showed promising activities. The cell inhibition studies were also performed and the target compound (**20**) exhibited a significant inhibition and exhibited EGFR kinase inhibitory activity (over ≥30%) against MCF7 cells. The molecular docking studies indicated that the target compound showed two-hydrogen bonding interactions with residues of LYS721 and THR830 at the binding site of EGFR tyrosine kinase [53]. Akhtar et al. reported the benzimidazole-oxadiazole hybrids as selective EGFR and erbB2 receptor inhibitors. In *in vitro* cell inhibition studies, the target compound (**21**) exhibited a significant inhibition with an IC50 of 5.0 μM against breast cancer (MCF-7) cells. The target compound was found to show significant inhibition of EGFR and erbB2 receptor at 0.081 and 0.098 μM respectively. Most of the synthesized compounds exhibited a good cytotoxic activity against selected human cancer cell lines. In cell cycle analysis, the target compound selectively arrested MCF-7 cell growth at the G2/M phase. The computational and 3D-QSAR studies indicated that the target compound exhibited strong interactions with Asp831, Met769, and Thr830 of the EGFR enzyme [54].

Akhtar et al. have synthesized benzimidazole-based pyrazole derivatives through a one-pot multicomponent reaction and evaluated them for their potential anticancer activities. The synthesized compounds were screened against selected human cancer cell lines such as MCF-7, MDA-MB231, A549, HepG2, and HaCaT. The evaluation of EGFR inhibitory activities was performed for all the synthesized compounds. The target compound (**22**) exhibited promising cytotoxicity against the lung (A549) cancer cell lines with an IC50 value of 2.2 mM and the EGFR receptor inhibition value with an IC50 of 0.97 mM. In cell cycle analysis, the target compound selectively arrested A549 cell growth at the G2/M phase. In addition, it suppressed the growth of lung cancer cells by inducing apoptosis. In molecular docking studies, the target compound showed strong electronic interactions with Met769, Thr830, Lys721, and Phe699 of the active pocket of the EGFR receptor [55]. Yuan et al. have synthesized a library of 6-amide-2-aryl benzoxazole/benzimidazole derivatives and evaluated them for their selective inhibitory activities against VEGFR-2. The library of compounds exhibited selective anticancer activity against the liver hepatocellular carcinoma (HepG2), and human umbilical vein endothelial cells (HUVECs) over the lung cancer (A549) and breast (MDA-MB-231) cancer

**Figure 5.**

*The benzimidazole derivatives as selective anticancer agents via targeting EGFR.*

cell lines. The target compound exhibited a significant growth inhibition against HepG2 and HUVEC with IC50 values of 1.47 and 2.57 mM, respectively. The target compound (**23**) showed anti-angiogenesis ability (79% inhibition at 10 nM/eggs) by chick chorioallantoic membrane (CAM) assay and exhibited excellent VEGFR-2 kinase inhibition with an IC50 of 0.051 mM. The computational analysis showed that the target compound made strong interactions with the active site of VEGFR-2 kinase. It is concluded that the 6-amide-2-arylbenzoxazole/benzimidazole derivatives are essential inhibitors of VEGFR-2 kinase for the treatment of anti-angiogenesis [56] (**Figure 5**).

#### **4. Miscellaneous agents**

Wu et al*.* synthesized a series of novel benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives and two representative compounds (**24**) and (**25**) showed significant inhibitory activity against colorectal (HCT116), breast (MCF-7), and liver (HepG2) cell lines, and effective inhibition of tumor growth in BALB/c mice with colon carcinoma HCT116 cells [57]. Reddy et al. reported a series of pyrazole-containing benzimidazole hybrids and evaluated them for their potential anti-proliferative activity against lung (A549), breast (MCF-7), and cervical (HeLa) cell lines. The compounds (**26**) and (**27**) showed potent growth inhibition against all the cell lines tested, with IC50 values in the range of 0.83–1.81 μM [58]. Gowda et al. synthesized a series of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives and the compound (**28**) induced maximum cell death in leukemic cells (K562 and CEM cell lines), through inducing apoptosis via S/G2 cell cycle arrest; down regulation of CDK2, Cyclin B1 and PCNA; cleavage of PARP; and elevated levels of DNA strand breaks [59]. Akhtar et al*.* reported a series of benzimidazole-linked oxadizole hybrids and the compounds were screened for their anticancer and *in vitro* EGFR and erbB2 receptor inhibition assay. Two of the compounds (**29**) and (**30**) displayed promising activity. The compound 70a showed EGFR inhibition and induced apoptosis by G2/M cell cycle arrest [54] (**Figure 6**).

#### **5. Synthetic strategies**

The first benzimidazole (2,5-dimethylbenzimidazole) (**3**) or 2,6-dimethylbenzimidazole (**4**) was prepared in 1872 by Hoebrecker through reduction of

**49**

**Figure 7.**

**Figure 6.**

*The novel benzimidazole derivatives as potential anticancer agents.*

*General syntheses of benzimidazoles from aniline derivatives.*

*Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents*

2-nitro-4-methylacetanilide [60] (**1**) (**Figure 7**). Several years later, the synthesis of benzimidazole was reported by refluxing 3,4-diamino toluene (**2**) with acetic acid [61]. Many synthetic ways toward the construction of benzimidazole ring started

*DOI: http://dx.doi.org/10.5772/intechopen.90758*

#### *Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents DOI: http://dx.doi.org/10.5772/intechopen.90758*

*Heterocycles - Synthesis and Biological Activities*

esis [56] (**Figure 5**).

**Figure 5.**

**4. Miscellaneous agents**

**5. Synthetic strategies**

cell lines. The target compound exhibited a significant growth inhibition against HepG2 and HUVEC with IC50 values of 1.47 and 2.57 mM, respectively. The target compound (**23**) showed anti-angiogenesis ability (79% inhibition at 10 nM/eggs) by chick chorioallantoic membrane (CAM) assay and exhibited excellent VEGFR-2 kinase inhibition with an IC50 of 0.051 mM. The computational analysis showed that the target compound made strong interactions with the active site of VEGFR-2 kinase. It is concluded that the 6-amide-2-arylbenzoxazole/benzimidazole derivatives are essential inhibitors of VEGFR-2 kinase for the treatment of anti-angiogen-

*The benzimidazole derivatives as selective anticancer agents via targeting EGFR.*

Wu et al*.* synthesized a series of novel benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives and two representative compounds (**24**) and (**25**) showed significant inhibitory activity against colorectal (HCT116), breast (MCF-7), and liver (HepG2) cell lines, and effective inhibition of tumor growth in BALB/c mice with colon carcinoma HCT116 cells [57]. Reddy et al. reported a series of pyrazole-containing benzimidazole hybrids and evaluated them for their potential anti-proliferative activity against lung (A549), breast (MCF-7), and cervical (HeLa) cell lines. The compounds (**26**) and (**27**) showed potent growth inhibition against all the cell lines tested, with IC50 values in the range of 0.83–1.81 μM [58]. Gowda et al. synthesized a series of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives and the compound (**28**) induced maximum cell death in leukemic cells (K562 and CEM cell lines), through inducing apoptosis via S/G2 cell cycle arrest; down regulation of CDK2, Cyclin B1 and PCNA; cleavage of PARP; and elevated levels of DNA strand breaks [59]. Akhtar et al*.* reported a series of benzimidazole-linked oxadizole hybrids and the compounds were screened for their anticancer and *in vitro* EGFR and erbB2 receptor inhibition assay. Two of the compounds (**29**) and (**30**) displayed promising activity. The compound 70a showed EGFR inhibition and induced apoptosis by G2/M cell cycle arrest [54] (**Figure 6**).

The first benzimidazole (2,5-dimethylbenzimidazole) (**3**) or 2,6-dimethylbenzimidazole (**4**) was prepared in 1872 by Hoebrecker through reduction of

**48**

*The novel benzimidazole derivatives as potential anticancer agents.*

**Figure 7.**

*General syntheses of benzimidazoles from aniline derivatives.*

2-nitro-4-methylacetanilide [60] (**1**) (**Figure 7**). Several years later, the synthesis of benzimidazole was reported by refluxing 3,4-diamino toluene (**2**) with acetic acid [61]. Many synthetic ways toward the construction of benzimidazole ring started

from commercially available benzene derivatives containing nitrogen functionalities, especially ortho derivatives. Hence, a number of methods have been reported for the synthesis of bioactive benzimidazoles and their derivatives. The majority of these involve the condensation of *O*-phenylene diamines (**5**) and its derivatives with carboxylic acids (**6**), esters, alcohols, or aldehydes [62].

Synthesis of benzimidazoles in the presence of various catalysts involves the condensation of *O*-phenylene diamines with *ortho* esters in the presence of Lewis acids like ZrCl4, SnCl4, TiCl4, HFCl4, etc. The most commonly used method for synthesis of benzimidazoles (**7**) is Phillip's method, which involves the condensation of *O*-phenylene diamines (**5**) with carboxylic acids (**6**) or its derivatives by heating the reagents in the presence of concentrated hydrochloric acid [62] (**Figure 8**).

The benzimidazole derivatives (**14**) were synthesized under mild conditions with inherently low cost by many researchers using (**8**), (**9**), (**10**), (**11**), (**12**), and (**13**), as reactants (**Figure 9**). Suheyla et al. demonstrated the synthesis of benzimidazoles by condensation of O-phenylene diamine with an appropriate aldehyde (**8**) in the presence of sodium metabisulfite. They proposed the reaction that depends on forming the bisulfite adduct of the aryl aldehyde to prepare benzimidazole.

Hanan et al. have reported one-pot conversion of aromatic and heteroaromatic 2-nitroamines (**9**) into bicyclic 2*H*-benzimidazoles employs formic acid, iron

**Figure 8.**

*Phillip's condensation for the synthesis of benzimidazoles.*

**51**

**Author details**

**6. Conclusion**

cytotoxic agents.

**Conflict of interest**

Authors declare "no conflict of interest."

(NIMHANS), India

Nerella Sridhar Goud\*, Pardeep Kumar and Rose Dawn Bharath

\*Address all correspondence to: sridhar.ku23@gmail.com

provided the original work is properly cited.

Department of Neuroimaging and Interventional Radiology (NI & IR),

Radiochemistry Facility, National Institute of Mental Health and Neuro Sciences

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents*

powder, and NH4Cl as an additive to reduce the nitro group and effect the imidazole cyclization with high-yields [63]. Nale et al*.* developed a method for the synthesis of benzimidazole derivatives in the presence of zinc catalysts from N-substituted formamides and various o-phenylenediamines [64] (**10**). Mahesh et al. developed a method of one-pot, multicomponent reaction, which enables the transformation of commercial aryl amines, aldehydes, and azides (**11**) into various benzimidazoles *via* an efficient copper-catalyzed amination of N-aryl imines [64]. Lin et al. developed a method for solvent/oxidant-switchable synthesis of multisubstituted benzimidazoles *via* metal-free selective oxidative annulation of arylamidines [65] (**12**). Wray et al. synthesized various *N*-aryl-1*H*-indazoles and benzimidazoles from common

There are numerous benzimidazole derivatives for various cancer types involving unique types of mechanism. Although it is a widely used pharmacophore, still very few target-specific benzimidazoles are available. Therefore, researchers across the world need to develop new benzimidazole derivatives that are more target specific and help in the cancer treatment to overcome non-selective toxicity and adverse effects. This chapter mainly focused on target-based benzimidazole derivatives and synthetic strategies. Hence, it would give more ideas to young medicinal researchers to develop target-specific benzimidazole derivatives as potential

*DOI: http://dx.doi.org/10.5772/intechopen.90758*

arylamino oximes (**13**) in good to excellent yields [66].

**Figure 9.** *Synthetic strategies of benzimidazoles.*

*Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents DOI: http://dx.doi.org/10.5772/intechopen.90758*

powder, and NH4Cl as an additive to reduce the nitro group and effect the imidazole cyclization with high-yields [63]. Nale et al*.* developed a method for the synthesis of benzimidazole derivatives in the presence of zinc catalysts from N-substituted formamides and various o-phenylenediamines [64] (**10**). Mahesh et al. developed a method of one-pot, multicomponent reaction, which enables the transformation of commercial aryl amines, aldehydes, and azides (**11**) into various benzimidazoles *via* an efficient copper-catalyzed amination of N-aryl imines [64]. Lin et al. developed a method for solvent/oxidant-switchable synthesis of multisubstituted benzimidazoles *via* metal-free selective oxidative annulation of arylamidines [65] (**12**). Wray et al. synthesized various *N*-aryl-1*H*-indazoles and benzimidazoles from common arylamino oximes (**13**) in good to excellent yields [66].

#### **6. Conclusion**

*Heterocycles - Synthesis and Biological Activities*

benzimidazole.

**Figure 8.**

*Phillip's condensation for the synthesis of benzimidazoles.*

carboxylic acids (**6**), esters, alcohols, or aldehydes [62].

from commercially available benzene derivatives containing nitrogen functionalities, especially ortho derivatives. Hence, a number of methods have been reported for the synthesis of bioactive benzimidazoles and their derivatives. The majority of these involve the condensation of *O*-phenylene diamines (**5**) and its derivatives with

Synthesis of benzimidazoles in the presence of various catalysts involves the condensation of *O*-phenylene diamines with *ortho* esters in the presence of Lewis acids like ZrCl4, SnCl4, TiCl4, HFCl4, etc. The most commonly used method for synthesis of benzimidazoles (**7**) is Phillip's method, which involves the condensation of *O*-phenylene diamines (**5**) with carboxylic acids (**6**) or its derivatives by heating the

The benzimidazole derivatives (**14**) were synthesized under mild conditions with inherently low cost by many researchers using (**8**), (**9**), (**10**), (**11**), (**12**), and (**13**), as reactants (**Figure 9**). Suheyla et al. demonstrated the synthesis of benzimidazoles by condensation of O-phenylene diamine with an appropriate aldehyde (**8**) in the presence of sodium metabisulfite. They proposed the reaction that depends on forming the bisulfite adduct of the aryl aldehyde to prepare

Hanan et al. have reported one-pot conversion of aromatic and heteroaromatic

2-nitroamines (**9**) into bicyclic 2*H*-benzimidazoles employs formic acid, iron

reagents in the presence of concentrated hydrochloric acid [62] (**Figure 8**).

**50**

**Figure 9.**

*Synthetic strategies of benzimidazoles.*

There are numerous benzimidazole derivatives for various cancer types involving unique types of mechanism. Although it is a widely used pharmacophore, still very few target-specific benzimidazoles are available. Therefore, researchers across the world need to develop new benzimidazole derivatives that are more target specific and help in the cancer treatment to overcome non-selective toxicity and adverse effects. This chapter mainly focused on target-based benzimidazole derivatives and synthetic strategies. Hence, it would give more ideas to young medicinal researchers to develop target-specific benzimidazole derivatives as potential cytotoxic agents.

#### **Conflict of interest**

Authors declare "no conflict of interest."

#### **Author details**

Nerella Sridhar Goud\*, Pardeep Kumar and Rose Dawn Bharath Department of Neuroimaging and Interventional Radiology (NI & IR), Radiochemistry Facility, National Institute of Mental Health and Neuro Sciences (NIMHANS), India

\*Address all correspondence to: sridhar.ku23@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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*Heterocycles - Synthesis and Biological Activities*

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[12] Kamanna K. Synthesis and pharmacological profile of

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2019;**26**

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1993;**36**(25):4040-4051

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[15] Sethi P, Bansal Y, Bansal G.

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Rizvi MA, Mehdi SH, et al. Therapeutic evolution of Benzimidazole derivatives in the last Quinquennial period. European Journal of Medicinal Chemistry. 2017;**126**:705-753

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Cancers. 2011;**3**(3):3279-3330

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[35] Lin B, Chen Z, Xu Y, Zhang H, Liu J, Qian X. 7-b, a novel Amonafide analogue, cause growth inhibition and apoptosis in Raji cells via a ROSmediated mitochondrial pathway. Leukemia Research. 2011;**35**(5):646-656

[36] Qian X, Li Z, Yang Q. Highly efficient antitumor agents of Heterocycles containing sulfur atom: Linear and angular Thiazonaphthalimides against human lung cancer cell in vitro. Bioorganic & Medicinal Chemistry. 2007;**15**(21):6846-6851

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[39] Wang Y-T, Shi T-Q, Zhu H-L, Liu C-H. Synthesis, biological evaluation and molecular docking of Benzimidazole grafted Benzsulfamidecontaining Pyrazole ring derivatives as novel tubulin polymerization inhibitors. Bioorganic & Medicinal Chemistry. 2019;**27**(3):502-515

[40] Baig MF, Nayak VL, Budaganaboyina P, Mullagiri K, Sunkari S, Gour J, et al. Synthesis and biological evaluation of Imidazo[2,1-b] Thiazole-Benzimidazole conjugates as microtubule-targeting agents. Bioorganic Chemistry. 2018;**77**:515-526

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against tumor cells by inhibiting VEGFR-2 kinase. European Journal of Medicinal Chemistry. 2019;**179**:147-165

[57] Wu L, Jiang Z, Shen J, Yi H, Zhan Y, Sha M, et al. Design, synthesis and biological evaluation of novel Benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives as antitumour agents. European Journal of Medicinal Chemistry. 2016;**114**:328-336

[58] Reddy TS, Kulhari H, Reddy VG, Bansal V, Kamal A, Shukla R. Design, synthesis and biological evaluation of 1,3-Diphenyl-1 H-Pyrazole derivatives containing Benzimidazole skeleton as potential anticancer and apoptosis inducing agents. European Journal of Medicinal Chemistry. 2015;**101**:790-805

[59] Gowda NRT, Kavitha CV, Chiruvella KK, Joy O, Rangappa KS, Raghavan SC. Synthesis and biological evaluation of novel 1-(4-Methoxyphenethyl)- 1H-Benzimidazole-5-carboxylic acid derivatives and their precursors as Antileukemic agents. Bioorganic & Medicinal Chemistry Letters.

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2012;**20**(21):6208-6236

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derivatives bearing Pyrazole as

*DOI: http://dx.doi.org/10.5772/intechopen.90758*

Matulis D. Benzenesulfonamides with Benzimidazole moieties as inhibitors of carbonic anhydrases I, II, VII, XII and XIII. Journal of Enzyme Inhibition and Medicinal Chemistry.

Lindberg RA. Receptor protein-tyrosine kinases and their signal transduction pathways. Annual Review of Cell Biology. 1994;**10**(1):251-337

2014;**29**(1):124-131

[48] van der Geer P, Hunter T,

[49] Schneider MR, Wolf E. The epidermal growth factor receptor ligands at a glance. Journal of Cellular Physiology. 2009;**218**(3):460-466

[51] Sigismund S, Avanzato D,

role of epidermal growth factor receptor in cancer metastasis and microenvironment. BioMed Research

International. 2013;**2013**:1-8

2018;**12**(1):3-20

[50] Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK. Targeting the EGFR signaling pathway in cancer therapy. Expert Opinion on Therapeutic Targets. 2012;**16**(1):15-31

Lanzetti L. Emerging functions of the EGFR in cancer. Molecular Oncology.

[52] Sasaki T, Hiroki K, Yamashita Y. The

[53] Celik İ, Ayhan-Kılcıgil G, Guven B, Kara Z, Gurkan-Alp AS, Karayel A, et al. Design, synthesis and docking studies of Benzimidazole derivatives as potential EGFR inhibitors. European Journal of Medicinal Chemistry. 2019;**173**:240-249

[54] Akhtar MJ, Siddiqui AA, Khan AA, Ali Z, Dewangan RP, Pasha S, et al. Design, synthesis, docking and QSAR study of substituted Benzimidazole linked Oxadiazole as cytotoxic agents, EGFR and ErbB2 receptor inhibitors. European Journal of Medicinal Chemistry. 2017;**126**:853-869

[55] Akhtar MJ, Khan AA, Ali Z, Dewangan RP, Rafi M, Hassan MQ, *Recent Developments of Target-Based Benzimidazole Derivatives as Potential Anticancer Agents DOI: http://dx.doi.org/10.5772/intechopen.90758*

Matulis D. Benzenesulfonamides with Benzimidazole moieties as inhibitors of carbonic anhydrases I, II, VII, XII and XIII. Journal of Enzyme Inhibition and Medicinal Chemistry. 2014;**29**(1):124-131

*Heterocycles - Synthesis and Biological Activities*

Bioorganic & Medicinal Chemistry.

Budaganaboyina P, Mullagiri K, Sunkari S, Gour J, et al. Synthesis and biological evaluation of Imidazo[2,1-b] Thiazole-Benzimidazole conjugates as microtubule-targeting agents. Bioorganic Chemistry. 2018;**77**:515-526

[41] Supuran CT. Carbonic anhydrases:

[42] Supuran C. Carbonic anhydrases an overview. Current Pharmaceutical

[43] Supuran CT, Winum J-Y. Carbonic anhydrase IX inhibitors in cancer therapy: An update. Future Medicinal Chemistry. 2015;**7**(11):1407-1414

[44] Supuran CT, Alterio V, Di Fiore A, D'Ambrosio K, Carta F, Monti SM, et al. Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the Price of one. Medicinal Research Reviews.

[45] Peng X-M, Damu GL, Zhou C. Current developments of Coumarin compounds in medicinal chemistry. Current Pharmaceutical Design.

[46] Milite C, Amendola G, Nocentini A, Bua S, Cipriano A, Barresi E, et al. Novel 2-substituted-Benzimidazole-6-sulfonamides as carbonic anhydrase inhibitors: Synthesis, biological evaluation against isoforms I, II, IX and XII and molecular docking studies. Journal of Enzyme

Inhibition and Medicinal Chemistry.

[47] Zubrienė A, Čapkauskaitė E, Gylytė J, Kišonaitė M, Tumkevičius S,

Novel therapeutic applications for inhibitors and activators. Nature Reviews Drug Discovery.

Design. 2008;**14**(7):603-614

2018;**38**(6):1799-1836

2013;**19**(21):3884-3930

2019;**34**(1):1697-1710

2008;**7**(2):168-181

2019;**27**(3):502-515

[40] Baig MF, Nayak VL,

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison Ethonafide (AMP-53, 6-Ethoxyazonafide). Biochemical Pharmacology. 2008;**75**(4):883-890

[34] Piao W-H, Wong R, Bai X-F, Huang J, Campagnolo DI, Dorr RT, et al. Therapeutic effect of Anthracenebased anticancer agent Ethonafide in an animal model of multiple sclerosis. The Journal of Immunology.

[35] Lin B, Chen Z, Xu Y, Zhang H, Liu J, Qian X. 7-b, a novel Amonafide analogue, cause growth inhibition and apoptosis in Raji cells via a ROSmediated mitochondrial pathway. Leukemia Research. 2011;**35**(5):646-656

2007;**179**(11):7415-7423

[36] Qian X, Li Z, Yang Q.

2007;**15**(21):6846-6851

Highly efficient antitumor agents of Heterocycles containing sulfur atom: Linear and angular Thiazonaphthalimides against human lung cancer cell in vitro. Bioorganic & Medicinal Chemistry.

[37] Zhang Y-L, Yang R, Xia L-Y, Man R-J, Chu Y-C, Jiang A-Q, et al. Synthesis, anticancer activity and molecular docking studies on 1,2-Diarylbenzimidazole analogues as anti-tubulin agents. Bioorganic Chemistry. 2019;**92**:103219

[38] Miao T-T, Tao X-B, Li D-D, Chen H, Jin X-Y, Geng Y, et al.

[39] Wang Y-T, Shi T-Q, Zhu H-L, Liu C-H. Synthesis, biological evaluation and molecular docking of Benzimidazole grafted Benzsulfamidecontaining Pyrazole ring derivatives as novel tubulin polymerization inhibitors.

Synthesis and biological evaluation of 2-aryl-Benzimidazole derivatives of Dehydroabietic acid as novel tubulin polymerization inhibitors. RSC Advances. 2018;**8**(31):17511-17526

**54**

[48] van der Geer P, Hunter T, Lindberg RA. Receptor protein-tyrosine kinases and their signal transduction pathways. Annual Review of Cell Biology. 1994;**10**(1):251-337

[49] Schneider MR, Wolf E. The epidermal growth factor receptor ligands at a glance. Journal of Cellular Physiology. 2009;**218**(3):460-466

[50] Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK. Targeting the EGFR signaling pathway in cancer therapy. Expert Opinion on Therapeutic Targets. 2012;**16**(1):15-31

[51] Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Molecular Oncology. 2018;**12**(1):3-20

[52] Sasaki T, Hiroki K, Yamashita Y. The role of epidermal growth factor receptor in cancer metastasis and microenvironment. BioMed Research International. 2013;**2013**:1-8

[53] Celik İ, Ayhan-Kılcıgil G, Guven B, Kara Z, Gurkan-Alp AS, Karayel A, et al. Design, synthesis and docking studies of Benzimidazole derivatives as potential EGFR inhibitors. European Journal of Medicinal Chemistry. 2019;**173**:240-249

[54] Akhtar MJ, Siddiqui AA, Khan AA, Ali Z, Dewangan RP, Pasha S, et al. Design, synthesis, docking and QSAR study of substituted Benzimidazole linked Oxadiazole as cytotoxic agents, EGFR and ErbB2 receptor inhibitors. European Journal of Medicinal Chemistry. 2017;**126**:853-869

[55] Akhtar MJ, Khan AA, Ali Z, Dewangan RP, Rafi M, Hassan MQ, et al. Synthesis of stable Benzimidazole derivatives bearing Pyrazole as anticancer and EGFR receptor inhibitors. Bioorganic Chemistry. 2018;**78**:158-169

[56] Yuan X, Yang Q, Liu T, Li K, Liu Y, Zhu C, et al. Design, synthesis and in vitro evaluation of 6-Amide-2-aryl Benzoxazole/Benzimidazole derivatives against tumor cells by inhibiting VEGFR-2 kinase. European Journal of Medicinal Chemistry. 2019;**179**:147-165

[57] Wu L, Jiang Z, Shen J, Yi H, Zhan Y, Sha M, et al. Design, synthesis and biological evaluation of novel Benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives as antitumour agents. European Journal of Medicinal Chemistry. 2016;**114**:328-336

[58] Reddy TS, Kulhari H, Reddy VG, Bansal V, Kamal A, Shukla R. Design, synthesis and biological evaluation of 1,3-Diphenyl-1 H-Pyrazole derivatives containing Benzimidazole skeleton as potential anticancer and apoptosis inducing agents. European Journal of Medicinal Chemistry. 2015;**101**:790-805

[59] Gowda NRT, Kavitha CV, Chiruvella KK, Joy O, Rangappa KS, Raghavan SC. Synthesis and biological evaluation of novel 1-(4-Methoxyphenethyl)- 1H-Benzimidazole-5-carboxylic acid derivatives and their precursors as Antileukemic agents. Bioorganic & Medicinal Chemistry Letters. 2009;**19**(16):4594-4600

[60] Bansal Y, Silakari O. The therapeutic journey of Benzimidazoles: A review. Bioorganic & Medicinal Chemistry. 2012;**20**(21):6208-6236

[61] Alaqeel SI. Synthetic approaches to Benzimidazoles from O-Phenylenediamine: A literature review. Journal of Saudi Chemical Society. 2017;**21**(2):229-237

[62] Hanan E, Chan B, Estrada A, Shore D, Lyssikatos J. Mild and general one-pot reduction and cyclization of aromatic and Heteroaromatic 2-Nitroamines to bicyclic 2H-Imidazoles. Synlett. 2010;**2010**(18):2759-2764

[63] Nale D, Bhanage B. N-substituted Formamides as C1-sources for the synthesis of Benzimidazole and Benzothiazole derivatives by using zinc catalysts. Synlett. 2015;**26**(20):2835-2842

[64] Mahesh D, Sadhu P, Punniyamurthy T. Copper(I)-catalyzed Regioselective Amination of N -aryl imines using TMSN 3 and TBHP: A route to substituted Benzimidazoles. The Journal of Organic Chemistry. 2015;**80**(3):1644-1650

[65] Lin J-P, Zhang F-H, Long Y-Q. Solvent/oxidant-switchable synthesis of multisubstituted Quinazolines and Benzimidazoles via metal-free selective oxidative annulation of Arylamidines. Organic Letters. 2014;**16**(11):2822-2825

[66] Wray BC, Stambuli JP. Synthesis of N -Arylindazoles and Benzimidazoles from a common intermediate. Organic Letters. 2010;**12**(20):4576-4579

**57**

**Chapter 5**

**Abstract**

*and Daniel Plano*

metal complexes, peptides, sulfur

**1. Introduction**

Thiazole Moiety: An Interesting

*Sandra Ramos-Inza, Carlos Aydillo, Carmen Sanmartín* 

Currently, cancer is one of the major health problems of the human population and prominent cause of death. Thiazole ring has demonstrated many pharmacological activities including anticancer. This scaffold has been found alone or incorporated into the diversity of therapeutic active agents such as tiazofurin, dasatinib, and bleomycin, which are well-known antineoplastic drugs. Recently, most of the compounds isolated from natural sources containing thiazole moiety exhibit notable cytotoxicities and present antitumor potential. In this context, several structural changes have been made in the original structure, such as the incorporation of different substituents or the fusion with other carbo- and heterocycles, in order to increase the antitumoral potency. Related to mechanism of action of these derivatives, some of them act through kinase modulation, polymerization inhibition of microtubule, pro-matrix metalloproteinase activation, signal transducer

Cancer is a generic term, which encompasses a wide group of diseases characterized essentially by an uncontrolled growth and propagation of cells with errors in the division mechanisms known as cell cycle. Cancer constitutes a major public health problem worldwide, since it is the second leading cause of death globally, with 9.6 million deaths estimated in 2018 [1]. Due to the limitations and side effects associated with available cancer treatments nowadays, it is an urgent challenge for

Among the design strategies in drug discovery, special attention has been paid to molecules containing sulfur heterocycles in their structures. Several studies have been carried out with plenty of sulfur heterocycles, including thiophene, thione,

Thiazole ring is present in several anticancer drugs, such as bleomycin, sulfathiazole, thiazofurine, and dasatinib, and its derivatives present excellent pharmacological profiles, making this skeleton an ideal candidate to develop more potent and

Scaffold for Developing New

Antitumoral Compounds

activation of transcription 3, histone deacetylase inhibition, etc.

**Keywords:** cancer, thiazole, MDM2 inhibitors, mechanism of action,

medicinal researchers to develop more safe and selective anticancer drugs.

benzothiophene, and thiazine, towards different pathologies.

#### **Chapter 5**

*Heterocycles - Synthesis and Biological Activities*

2-Nitroamines to bicyclic 2H-Imidazoles.

[63] Nale D, Bhanage B. N-substituted Formamides as C1-sources for the synthesis of Benzimidazole and Benzothiazole derivatives by using zinc catalysts. Synlett.

[64] Mahesh D, Sadhu P, Punniyamurthy T. Copper(I)-catalyzed Regioselective Amination of N -aryl imines using TMSN 3 and TBHP: A route to substituted Benzimidazoles. The Journal of Organic Chemistry.

one-pot reduction and cyclization of aromatic and Heteroaromatic

Synlett. 2010;**2010**(18):2759-2764

2015;**26**(20):2835-2842

2015;**80**(3):1644-1650

[65] Lin J-P, Zhang F-H, Long Y-Q. Solvent/oxidant-switchable synthesis of multisubstituted Quinazolines and Benzimidazoles via metal-free selective oxidative annulation of Arylamidines. Organic Letters. 2014;**16**(11):2822-2825

[66] Wray BC, Stambuli JP. Synthesis of N -Arylindazoles and Benzimidazoles from a common intermediate. Organic

Letters. 2010;**12**(20):4576-4579

**56**

## Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds

*Sandra Ramos-Inza, Carlos Aydillo, Carmen Sanmartín and Daniel Plano*

#### **Abstract**

Currently, cancer is one of the major health problems of the human population and prominent cause of death. Thiazole ring has demonstrated many pharmacological activities including anticancer. This scaffold has been found alone or incorporated into the diversity of therapeutic active agents such as tiazofurin, dasatinib, and bleomycin, which are well-known antineoplastic drugs. Recently, most of the compounds isolated from natural sources containing thiazole moiety exhibit notable cytotoxicities and present antitumor potential. In this context, several structural changes have been made in the original structure, such as the incorporation of different substituents or the fusion with other carbo- and heterocycles, in order to increase the antitumoral potency. Related to mechanism of action of these derivatives, some of them act through kinase modulation, polymerization inhibition of microtubule, pro-matrix metalloproteinase activation, signal transducer activation of transcription 3, histone deacetylase inhibition, etc.

**Keywords:** cancer, thiazole, MDM2 inhibitors, mechanism of action, metal complexes, peptides, sulfur

#### **1. Introduction**

Cancer is a generic term, which encompasses a wide group of diseases characterized essentially by an uncontrolled growth and propagation of cells with errors in the division mechanisms known as cell cycle. Cancer constitutes a major public health problem worldwide, since it is the second leading cause of death globally, with 9.6 million deaths estimated in 2018 [1]. Due to the limitations and side effects associated with available cancer treatments nowadays, it is an urgent challenge for medicinal researchers to develop more safe and selective anticancer drugs.

Among the design strategies in drug discovery, special attention has been paid to molecules containing sulfur heterocycles in their structures. Several studies have been carried out with plenty of sulfur heterocycles, including thiophene, thione, benzothiophene, and thiazine, towards different pathologies.

Thiazole ring is present in several anticancer drugs, such as bleomycin, sulfathiazole, thiazofurine, and dasatinib, and its derivatives present excellent pharmacological profiles, making this skeleton an ideal candidate to develop more potent and safer drugs, especially in cancer. Herein, an extensive revision of the most relevant research published in the past 5 years is gathered.

#### **2. Thiazole rings decorated with different fragments**

#### **2.1 Thiazole derivatives with** *in vitro* **efficacy**

**Aminothiazoles**: Aminothiazoles have been widely used in drug discovery research due to its biological properties. Commercial drugs, such as famotidine, sudoxicam, or cefdinir, contain an aminothiazole core in their structures (**Figure 1**) [2].

Aminothiazole scaffold can be modified by derivatization of the amino group at position 2 of the thiazole ring. Rostom et al. [3] reported a study based on structural modifications including azomethine, *N*-formyl, *N*-acyl, sulfonamide, ureido, and thioureido functionalities. Nine derivatives were evaluated by the NCI *in vitro* screening panel assay, displaying most of them a promising antitumor activity against particular cell lines.

Sun et al. [4] synthesized a series of *N*,4-diaryl-1,3-thiazole-2-amines containing three aromatic rings with an amino linker. Compound **1** (**Figure 2**) was the most cytotoxic agent with IC50 values at the submicromolar level. A further biological evaluation showed that this compound inhibited polymerization and disrupted tubulin microtubule dynamics in a similar way to the natural product combretastatin A-4, besides effectively inducing SGC-7901 cell cycle arrest at the G2/M phase.

In other study, a series of tri-substituted aminothiazoles were designed by Lu et al. [5] in order to obtain new antitumoral agents. Compound **2** (**Figure 2**) displayed a EC50 value of 0.11 μM in hepatocellular carcinoma along with a selectivity towards nontumoral cells greater than 450 times.

A dysregulation of sirtuin 2 (Sirt2) plays an important role in the pathogenesis of cancer, among other diseases. Schiedel et al. [6] designed a series of novel aminothiazole derivatives with the aim of establishing a well-defined SAR model of sirtuin ligands. These thiazole-bearing compounds behaved as selective human sirtuins (hSirt2) inhibitors.

**Chalcones**: Chalcones are naturally biarylpropenones, which are classified as a subgroup of flavonoids with a broad spectrum of biological activities, including antimicrobial, anti-inflammatory, and anticancer properties [7].

A series of 4-amino-5-cinnamoylthiazoles as chalcone-like structures were synthesized and evaluated as antitumor agents, showing most of them significant cytotoxic activity against MCF-7, HepG2, and SW480 cell lines [8]. The most promising analog, compound **3** (**Figure 2**), revealed that it could prevent the proliferation of HepG2 cells by blocking cell cycle at the G2 phase and by inducing apoptosis.

**Coumarins**: Another strategy of design is the incorporation of a coumarin moiety in molecules containing thiazole. Many coumarin-bearing compounds are reported to have significant therapeutic potential, including anticancer activity

**59**

cell lines.

**Figure 2.**

the G1-phase.

discussed herein.

to be tested in clinical trials.

*Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds*

through different mechanisms. Jashari et al. [9] reported the synthesis of new derivatives by combining this coumarin core with different heterocycles. The results showed that the compounds containing thiazoles in the structure had the most

This strategy can be complementary with the inclusion of other structures with recognized biological activities. A series of indole-incorporated thiazolylcoumarins were synthesized and evaluated against a wide range of tumor cell lines [10]. Among the tested compounds, structure **4** (**Figure 2**) exhibited a broad spectrum of growth inhibition activity with average GI50 values of 1.18–2.44 μM against nine

Ayati et al. [11] also reported the synthesis of a series of new coumarin-containing compounds developed from the chalcone-like cinnamoylthiazoles mentioned above. Biological evaluations on the most cytotoxic compound **5** (**Figure 2**) against MCF-7 cells revealed the induction of apoptosis and blockage of the cell cycle distribution at

For the past 5 years, few examples of scaffolds bearing a thiazole ring have been reported with potent efficacy in xenograft models of various types of cancer. **Figure 3** encompasses the most relevant examples gathered in the literature that are going to be

Attending to their structure, the thiazole analogs can be grouped as follows. **Diaminothiazoles**: In 2015, several diaminothiazole derivatives were evaluated *in vitro* against wild-type and resistant colon, breast, and uterine cancer cells lines. All of them showed potent activity in all cell lines with IC50 values in the nanomolar range. Among them, DAT1 (4-amino-5-benzoyl-2-(4-methoxyphenylamino)thiazole) (**Figure 3**) also demonstrated *in vivo* tumor growth inhibition of around 60% in a taxol-resistant colon cancer model at a dose of 20 mg/kg [12]. More recently, DAT1 has also demonstrated its capacity to induce apoptosis both *in vitro* and *in vivo* against colon cancer models with mutated p53 through ERK-mediated upregulation of death receptor 5 (DR5) [13]. All these findings have placed DAT1 as a candidate

**(Thiazole-2-yl)hydrazones**: Di Martile et al*.* reported that a novel pCAF and GCN5 histone deacetylase inhibitor, named CPTH6 (3-methylcyclopentylidene- [4-(4′-chlorophenyl)thiazol-2-yl] hydrazone) (**Figure 3**), was able to reduce tumor growth in a spheroid patient-derived lung cancer stem cells (LCSCs) xenograft model

promising activity against the cancer cell lines tested.

**2.2 Thiazole derivatives with** *in vivo* **efficacy**

*DOI: http://dx.doi.org/10.5772/intechopen.82741*

*Thiazole derivatives as potential antitumor agents.*

**Figure 1.** *Some aminothiazole as commercial drugs.*

*Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds DOI: http://dx.doi.org/10.5772/intechopen.82741*

**Figure 2.**

*Heterocycles - Synthesis and Biological Activities*

research published in the past 5 years is gathered.

**2.1 Thiazole derivatives with** *in vitro* **efficacy**

ity towards nontumoral cells greater than 450 times.

against particular cell lines.

sirtuins (hSirt2) inhibitors.

**2. Thiazole rings decorated with different fragments**

cefdinir, contain an aminothiazole core in their structures (**Figure 1**) [2].

safer drugs, especially in cancer. Herein, an extensive revision of the most relevant

**Aminothiazoles**: Aminothiazoles have been widely used in drug discovery research due to its biological properties. Commercial drugs, such as famotidine, sudoxicam, or

Aminothiazole scaffold can be modified by derivatization of the amino group at position 2 of the thiazole ring. Rostom et al. [3] reported a study based on structural modifications including azomethine, *N*-formyl, *N*-acyl, sulfonamide, ureido, and thioureido functionalities. Nine derivatives were evaluated by the NCI *in vitro* screening panel assay, displaying most of them a promising antitumor activity

Sun et al. [4] synthesized a series of *N*,4-diaryl-1,3-thiazole-2-amines containing three aromatic rings with an amino linker. Compound **1** (**Figure 2**) was the most cytotoxic agent with IC50 values at the submicromolar level. A further biological evaluation showed that this compound inhibited polymerization and disrupted tubulin microtubule dynamics in a similar way to the natural product combretastatin A-4, besides effectively inducing SGC-7901 cell cycle arrest at the G2/M phase. In other study, a series of tri-substituted aminothiazoles were designed by Lu et al. [5] in order to obtain new antitumoral agents. Compound **2** (**Figure 2**) displayed a EC50 value of 0.11 μM in hepatocellular carcinoma along with a selectiv-

A dysregulation of sirtuin 2 (Sirt2) plays an important role in the pathogenesis

**Chalcones**: Chalcones are naturally biarylpropenones, which are classified as a subgroup of flavonoids with a broad spectrum of biological activities, including

A series of 4-amino-5-cinnamoylthiazoles as chalcone-like structures were synthesized and evaluated as antitumor agents, showing most of them significant cytotoxic activity against MCF-7, HepG2, and SW480 cell lines [8]. The most promising analog, compound **3** (**Figure 2**), revealed that it could prevent the proliferation of HepG2 cells by blocking cell cycle at the G2 phase and by inducing apoptosis. **Coumarins**: Another strategy of design is the incorporation of a coumarin moiety in molecules containing thiazole. Many coumarin-bearing compounds are reported to have significant therapeutic potential, including anticancer activity

of cancer, among other diseases. Schiedel et al. [6] designed a series of novel aminothiazole derivatives with the aim of establishing a well-defined SAR model of sirtuin ligands. These thiazole-bearing compounds behaved as selective human

antimicrobial, anti-inflammatory, and anticancer properties [7].

**58**

**Figure 1.**

*Some aminothiazole as commercial drugs.*

*Thiazole derivatives as potential antitumor agents.*

through different mechanisms. Jashari et al. [9] reported the synthesis of new derivatives by combining this coumarin core with different heterocycles. The results showed that the compounds containing thiazoles in the structure had the most promising activity against the cancer cell lines tested.

This strategy can be complementary with the inclusion of other structures with recognized biological activities. A series of indole-incorporated thiazolylcoumarins were synthesized and evaluated against a wide range of tumor cell lines [10]. Among the tested compounds, structure **4** (**Figure 2**) exhibited a broad spectrum of growth inhibition activity with average GI50 values of 1.18–2.44 μM against nine cell lines.

Ayati et al. [11] also reported the synthesis of a series of new coumarin-containing compounds developed from the chalcone-like cinnamoylthiazoles mentioned above. Biological evaluations on the most cytotoxic compound **5** (**Figure 2**) against MCF-7 cells revealed the induction of apoptosis and blockage of the cell cycle distribution at the G1-phase.

#### **2.2 Thiazole derivatives with** *in vivo* **efficacy**

For the past 5 years, few examples of scaffolds bearing a thiazole ring have been reported with potent efficacy in xenograft models of various types of cancer. **Figure 3** encompasses the most relevant examples gathered in the literature that are going to be discussed herein.

Attending to their structure, the thiazole analogs can be grouped as follows.

**Diaminothiazoles**: In 2015, several diaminothiazole derivatives were evaluated *in vitro* against wild-type and resistant colon, breast, and uterine cancer cells lines. All of them showed potent activity in all cell lines with IC50 values in the nanomolar range. Among them, DAT1 (4-amino-5-benzoyl-2-(4-methoxyphenylamino)thiazole) (**Figure 3**) also demonstrated *in vivo* tumor growth inhibition of around 60% in a taxol-resistant colon cancer model at a dose of 20 mg/kg [12]. More recently, DAT1 has also demonstrated its capacity to induce apoptosis both *in vitro* and *in vivo* against colon cancer models with mutated p53 through ERK-mediated upregulation of death receptor 5 (DR5) [13]. All these findings have placed DAT1 as a candidate to be tested in clinical trials.

**(Thiazole-2-yl)hydrazones**: Di Martile et al*.* reported that a novel pCAF and GCN5 histone deacetylase inhibitor, named CPTH6 (3-methylcyclopentylidene- [4-(4′-chlorophenyl)thiazol-2-yl] hydrazone) (**Figure 3**), was able to reduce tumor growth in a spheroid patient-derived lung cancer stem cells (LCSCs) xenograft model

#### **Figure 3.**

*Representative scaffolds containing thiazole ring with proven in vivo efficacy towards several cancer xenograft models.*

accompanied by apoptosis induction and inhibition of α-tubulin acetylation [14]. Likewise, two 2-pyridyl-2,3-thiazole derivatives, TP-07 and TAP-07 (**Figure 3**), possess cytotoxic activity towards several cancer cell lines without antiproliferative effects to normal cells (IC50 > 30 μM) along with *in vivo* efficacy against a hepatocellular xenograft cancer model [15]. Thus, both compounds achieved 47% and 73% tumor mass reduction, respectively [15].

**Spiroimidazothiazolidines**: This class of compounds has demonstrated to be potent inhibitors of the Murine Double Minute-2 (MDM2)-p53 interaction, which ultimately leads to induction of apoptosis. Two analogs withstand in this class of compounds: a) ISA27 (**Figure 3**), which not only presented tumor growth inhibition *in vivo* alone in a glioblastoma xenograft model but also a synergistic effect with temozolomide, a first-line treatment drug against brain cancers [16], and b) SM13 (**Figure 3**), an analog that reduced tumor growth in a human thyroid cancer xenograft model in the absence of p53 transcriptional activity [17].

**Piperidinone analogs**: Based on previous morpholine and piperidone MDM2 inhibitors, Gonzalez et al*.* introduced a thiazole ring decorated with a carboxylic acid over the piperidone scaffold. The resulting hit compound, termed AM-6761 (**Figure 3**), maintained the MDM2 inhibition efficacy and presented an ED50 value of 11 mg/kg in SJSA-1 osteosarcoma xenograft model [18].

**Oridonin derivatives**: Oridonin is a complex ent-kaurane diterpenoid isolated from the traditional Chinese herb *Isodon rubescens*, with well-known cytotoxic activity against various human cancers. In 2013, Ding et al*.* designed a series of novel nitrogen-enriched oridonin derivatives with thiazole-fused A-ring. The hit compound, CYD0618 (**Figure 3**), induced a threefold shrinkage of the tumor volume in a triple-negative breast cancer MDA-MB-231 xenograft model at a dose of 5 mg/kg, showing much higher efficacy than parent oridonin [19]. Later, Zhou et al. reported another oridonin analog, CYD-6-17 (**Figure 3**), which significantly inhibited renal cell carcinoma tumor growth *in vivo* by targeting 3-phosphoinositide-dependent protein kinase 1 (PDPK1) and its downstream pathways [20].

**61**

**Figure 4.**

*Some thiazole-fused compounds with antitumor activity.*

*Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds*

**Benzothiazoles**: In the last few years, benzothiazoles have attracted considerable interest due to their broad spectrum of pharmacological activities, such as

This moiety can be functionalized with several structural modifications. Novel methylsulfonyl benzothiazoles were synthetized and evaluated against HeLA cell line, with compounds **6** and **7** (**Figure 4**) showing GI50 values of 0.1 μM or below [22]. Xie et al. [23] reported a new series of benzothiazole derivatives, with *in vitro*

Benzothiazole derivatives bearing pyrimidine moiety were synthetized and evaluated for anticancer activity against MCF-7, A549, and A375 cancer cell lines, with significant antitumor activity. A further study of the most promising compounds indicated an effect on the expression of proteins that cause abnormal cell

This moiety can also be used in the design of new molecules with a chalconelike structure, as it has been mentioned before. Imidazole bearing benzothiazoles were synthetized by Sultana et al. [25] and evaluated against several cancer cell lines. Compounds **9** and **10** (**Figure 4**) exhibited good cytotoxicity against human breast cancer (MDA MB-231) with IC50 values of 1.3 and 1.2 μM, respectively. These compounds were revealed to induce cell cycle arrest in G2/M phase and to inhibit

**Imidazoles**: Imidazole-based compounds have achieved great progress in medicinal chemistry, since they have showed anticancer, antifungal, antibacterial, and antiparasitic activities, among others [26]. Their use as heterocycles merged with thiazole has attracted great attention in the last years [27, 28] due to its therapeutic properties. A series of imidazo[2,1-*b*]thiazole derivatives were evaluated against different tumor cell lines, showing that compounds **11** and **12** (**Figure 4**) had a significant cytotoxic activity against A549 with IC50 values of 0.92 and 0.78 μM, respectively. These derivatives had proven to induce cell cycle arrest in G2/M phase and apoptosis in this cell line [29]. Ali et al. [30] synthesized a series of imidazo[2,1-*b*]thiazoles decorated with pyrazoles that turned out to be promising leads to further develop.

**3. Fused thiazole rings decorated with different fragments**

antitubercular, antimicrobial, analgesic, and antitumor properties [21].

efficacy against HCT116, MCF-7, U87 MG, and A549 cell lines. Compound **8** (**Figure 4**) was proved to retain the antiproliferative activity and the inhibitory activity against PI3K (phosphoinositide 3-kinase) and mTORC1 (mammalian target

of rapamycin), which are abnormally active in many tumor cells.

proliferation, such as ERK1/2, NF-kB, and survivin [24].

microtubule assembly.

*DOI: http://dx.doi.org/10.5772/intechopen.82741*

*Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds DOI: http://dx.doi.org/10.5772/intechopen.82741*

#### **3. Fused thiazole rings decorated with different fragments**

**Benzothiazoles**: In the last few years, benzothiazoles have attracted considerable interest due to their broad spectrum of pharmacological activities, such as antitubercular, antimicrobial, analgesic, and antitumor properties [21].

This moiety can be functionalized with several structural modifications. Novel methylsulfonyl benzothiazoles were synthetized and evaluated against HeLA cell line, with compounds **6** and **7** (**Figure 4**) showing GI50 values of 0.1 μM or below [22].

Xie et al. [23] reported a new series of benzothiazole derivatives, with *in vitro* efficacy against HCT116, MCF-7, U87 MG, and A549 cell lines. Compound **8** (**Figure 4**) was proved to retain the antiproliferative activity and the inhibitory activity against PI3K (phosphoinositide 3-kinase) and mTORC1 (mammalian target of rapamycin), which are abnormally active in many tumor cells.

Benzothiazole derivatives bearing pyrimidine moiety were synthetized and evaluated for anticancer activity against MCF-7, A549, and A375 cancer cell lines, with significant antitumor activity. A further study of the most promising compounds indicated an effect on the expression of proteins that cause abnormal cell proliferation, such as ERK1/2, NF-kB, and survivin [24].

This moiety can also be used in the design of new molecules with a chalconelike structure, as it has been mentioned before. Imidazole bearing benzothiazoles were synthetized by Sultana et al. [25] and evaluated against several cancer cell lines. Compounds **9** and **10** (**Figure 4**) exhibited good cytotoxicity against human breast cancer (MDA MB-231) with IC50 values of 1.3 and 1.2 μM, respectively. These compounds were revealed to induce cell cycle arrest in G2/M phase and to inhibit microtubule assembly.

**Imidazoles**: Imidazole-based compounds have achieved great progress in medicinal chemistry, since they have showed anticancer, antifungal, antibacterial, and antiparasitic activities, among others [26]. Their use as heterocycles merged with thiazole has attracted great attention in the last years [27, 28] due to its therapeutic properties.

A series of imidazo[2,1-*b*]thiazole derivatives were evaluated against different tumor cell lines, showing that compounds **11** and **12** (**Figure 4**) had a significant cytotoxic activity against A549 with IC50 values of 0.92 and 0.78 μM, respectively. These derivatives had proven to induce cell cycle arrest in G2/M phase and apoptosis in this cell line [29]. Ali et al. [30] synthesized a series of imidazo[2,1-*b*]thiazoles decorated with pyrazoles that turned out to be promising leads to further develop.

#### **Figure 4.**

*Some thiazole-fused compounds with antitumor activity.*

*Heterocycles - Synthesis and Biological Activities*

mass reduction, respectively [15].

**Figure 3.**

*models.*

accompanied by apoptosis induction and inhibition of α-tubulin acetylation [14]. Likewise, two 2-pyridyl-2,3-thiazole derivatives, TP-07 and TAP-07 (**Figure 3**), possess cytotoxic activity towards several cancer cell lines without antiproliferative effects to normal cells (IC50 > 30 μM) along with *in vivo* efficacy against a hepatocellular xenograft cancer model [15]. Thus, both compounds achieved 47% and 73% tumor

*Representative scaffolds containing thiazole ring with proven in vivo efficacy towards several cancer xenograft* 

**Spiroimidazothiazolidines**: This class of compounds has demonstrated to be potent inhibitors of the Murine Double Minute-2 (MDM2)-p53 interaction, which ultimately leads to induction of apoptosis. Two analogs withstand in this class of compounds: a) ISA27 (**Figure 3**), which not only presented tumor growth inhibition *in vivo* alone in a glioblastoma xenograft model but also a synergistic effect with temozolomide, a first-line treatment drug against brain cancers [16], and b) SM13 (**Figure 3**), an analog that reduced tumor growth in a human thyroid cancer xenograft model in the absence of p53 transcriptional activity [17].

**Piperidinone analogs**: Based on previous morpholine and piperidone MDM2 inhibitors, Gonzalez et al*.* introduced a thiazole ring decorated with a carboxylic acid over the piperidone scaffold. The resulting hit compound, termed AM-6761 (**Figure 3**), maintained the MDM2 inhibition efficacy and presented an ED50 value

**Oridonin derivatives**: Oridonin is a complex ent-kaurane diterpenoid isolated from the traditional Chinese herb *Isodon rubescens*, with well-known cytotoxic activity against various human cancers. In 2013, Ding et al*.* designed a series of novel nitrogen-enriched oridonin derivatives with thiazole-fused A-ring. The hit compound, CYD0618 (**Figure 3**), induced a threefold shrinkage of the tumor volume in a triple-negative breast cancer MDA-MB-231 xenograft model at a dose of 5 mg/kg, showing much higher efficacy than parent oridonin [19]. Later, Zhou et al. reported another oridonin analog, CYD-6-17 (**Figure 3**), which significantly inhibited renal cell carcinoma tumor growth *in vivo* by targeting 3-phosphoinositide-dependent protein kinase 1 (PDPK1) and its

of 11 mg/kg in SJSA-1 osteosarcoma xenograft model [18].

**60**

downstream pathways [20].

Due to the pharmacological properties of the imidazo[2,1-*b*]thiazole derivatives and coumarin compounds already mentioned, it has been reported a design that embodied both the active pharmacophores in a single molecule in order to evaluate their synergic activity against a series of tumor cell lines [31], showing some of them prominent cytotoxic activity.

Kamal et al. [32] also designed a novel series of imidazole merged with thiazole as chalcone-like derivatives and evaluated their cytotoxic activity against MCF-7, A549, HeLA, DU-145, and HT-29 cell lines. Among the compounds tested, structure **13** (**Figure 4**) with a pyridyl ring was the most active. This compound also disrupted microtubule dynamics, induced cell cycle arrest in G2/M phase and ultimately trigger apoptosis.

**Pyrimidines**: Compounds with fused rings can also be formed by merging other heterocyclic moieties with thiazole core. Li et al. [33] reported a novel series of thiazolo[5,4-*d*]pyrimidine derivatives, which were evaluated against three cancer cell lines. Compound **14** (**Figure 4**) showed the most potent antiproliferative activity with good selectivity when compared to normal cells (IC50 values of 1.03 μM against MGC803 and 38.95 μM against GES-1). Biological studies indicated that this compound could inhibit the cell colony formation and migration by inducing apoptosis on MGC803 cells.

A series of thiazolo[3,2-*a*]pyrimidines were synthetized and evaluated in the NCI-60 cell lines panel assay, achieving significant cytotoxicity against some of the cell lines tested [34].

#### **4. Miscellaneous structures bearing thiazole ring**

**Diazepines**: Heterocyclic compounds 1,4-diazepines are considered an interesting moiety in drug research due to their broad range of pharmacological activities, including antibacterial, anti-HIV, anticonvulsant, and anticancer [35]. Ramírez et al. designed a series of novel thiazole-based compounds by fusing this structure with pyrimidine, which has also showed biological properties. The results indicated that some compounds showed promising antitumoral activity, with GI50 values below 2 μM against NCI's *in vitro* cell line screening [35].

**Pyrazoline**: Another heterocyclic structure used in combination with thiazole moiety is the pyrazoline ring. New thiazolyl-pyrazoline derivatives were synthetized, and their cytotoxicity was evaluated against A549 human lung adenocarcinoma and NIH/3 T3 mouse embryonic fibroblast cells, presenting in some cases similar IC50 values to cisplatin [36].

**Curcumins**: Bayomi et al. [37] synthetized and evaluated a series of new curcumin analogs bearing thiazole as antitumoral and antioxidant agents, showing similar behavior than that of cisplatin and ascorbic acid, respectively.

**Thiazolines**: Thiazolines are the reduced form of thiazole and also have attracted interest in drug research due to its biological activity. Altintop et al. [38] evaluated a series of new thiazoline-based derivatives bearing a hydrazone moiety. The results showed that some of the compounds were potent inhibitors of DNA synthesis against C6 tumor cells.

#### **5. Thiazole and metal complexes**

There is a great variability of transition metals that in combination with different ligands have been reported as antitumoral agents acting through different mechanisms. The literature revealed the considerable interest in the thiazole

**63**

**Figure 5.**

*Some thiazole-metal complexes with antitumor activity.*

*Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds*

pharmacophore alone [39], fused to other rings [40], or incorporated into different

On the other hand, among the most effective and well-studied class of chemotherapeutic agents are the platinum-based drugs, which comprise cisplatin, carboplatin, and oxaliplatin. Given the clinical success of the platinum-based drugs, extensive research efforts have been made to develop alternative metal ions, that is, ruthenium,

**Copper complexes**: Copper complexes have attracted a vast interest due to their bioavailability, increased uptake in cancerous tissues, role in angiogenesis and photophysical properties, among others. The most common types of copper complexes are those incorporating 1,10-phenanthroline (phen) ligands. Planarity of the intercalative ligand is crucial in the binding of these complexes with DNA. The

Besides, Shakir et al. [43] have reported several Cu (II) complexes derived from

Studies carried out with several Cu (II) complexes with 2,2,6′,2′′-terpyridines revealed that these complexes are able to promote the generation of reactive oxygen species (ROS) in the presence of mild reducing agents. This feature has been exploited to oxidatively break the DNA strands, hence inhibiting the proliferation of tumor cells. In this context, the replacement of two pyridine rings by two thiazole nuclei (compound **15** in **Figure 5**) also achieved efficient DNA cleavage in several tumor cell lines [44]. Later, Czerwinska et al*.* corroborated an increase in the antiproliferative effect of these complexes against ovarian carcinoma cells by

In addition, the copper complexes have been recognized as promising drugs for metastatic tumors. For example, copper complexes of pyrrolidine dithiocarbamate (Cu(PDTC)2) possessed potent anticancer activity on cisplatin-resistant neuroblastoma cells. Additionally, two copper thiosemicarbazone complexes showed similar effect on cisplatin-resistant neuroblastoma cells and prostate cancer. Xie et al*.* [46] reported the synthesis and antitumoral activity of two copper complexes of (4*R*)- 2-thioxo-4-thiazolidinecarboxylic acid (TTDC) and 3-rhodaninepropionic acid (RDPA) against prostate cancer, presenting both of them variable potency, likely

benzothiazole and thiazole, which showed greater antioxidant and anticancer

complexes containing nonplanar ligands favored groove binding [42].

activities than the corresponding free ligands in various cell lines.

*DOI: http://dx.doi.org/10.5772/intechopen.82741*

copper, zinc, and nickel, with antitumor activity.

structures [41] for cancer therapy.

apoptosis [45].

#### *Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds DOI: http://dx.doi.org/10.5772/intechopen.82741*

pharmacophore alone [39], fused to other rings [40], or incorporated into different structures [41] for cancer therapy.

On the other hand, among the most effective and well-studied class of chemotherapeutic agents are the platinum-based drugs, which comprise cisplatin, carboplatin, and oxaliplatin. Given the clinical success of the platinum-based drugs, extensive research efforts have been made to develop alternative metal ions, that is, ruthenium, copper, zinc, and nickel, with antitumor activity.

**Copper complexes**: Copper complexes have attracted a vast interest due to their bioavailability, increased uptake in cancerous tissues, role in angiogenesis and photophysical properties, among others. The most common types of copper complexes are those incorporating 1,10-phenanthroline (phen) ligands. Planarity of the intercalative ligand is crucial in the binding of these complexes with DNA. The complexes containing nonplanar ligands favored groove binding [42].

Besides, Shakir et al. [43] have reported several Cu (II) complexes derived from benzothiazole and thiazole, which showed greater antioxidant and anticancer activities than the corresponding free ligands in various cell lines.

Studies carried out with several Cu (II) complexes with 2,2,6′,2′′-terpyridines revealed that these complexes are able to promote the generation of reactive oxygen species (ROS) in the presence of mild reducing agents. This feature has been exploited to oxidatively break the DNA strands, hence inhibiting the proliferation of tumor cells. In this context, the replacement of two pyridine rings by two thiazole nuclei (compound **15** in **Figure 5**) also achieved efficient DNA cleavage in several tumor cell lines [44]. Later, Czerwinska et al*.* corroborated an increase in the antiproliferative effect of these complexes against ovarian carcinoma cells by apoptosis [45].

In addition, the copper complexes have been recognized as promising drugs for metastatic tumors. For example, copper complexes of pyrrolidine dithiocarbamate (Cu(PDTC)2) possessed potent anticancer activity on cisplatin-resistant neuroblastoma cells. Additionally, two copper thiosemicarbazone complexes showed similar effect on cisplatin-resistant neuroblastoma cells and prostate cancer. Xie et al*.* [46] reported the synthesis and antitumoral activity of two copper complexes of (4*R*)- 2-thioxo-4-thiazolidinecarboxylic acid (TTDC) and 3-rhodaninepropionic acid (RDPA) against prostate cancer, presenting both of them variable potency, likely

**Figure 5.** *Some thiazole-metal complexes with antitumor activity.*

*Heterocycles - Synthesis and Biological Activities*

them prominent cytotoxic activity.

ultimately trigger apoptosis.

apoptosis on MGC803 cells.

cell lines tested [34].

Due to the pharmacological properties of the imidazo[2,1-*b*]thiazole derivatives and coumarin compounds already mentioned, it has been reported a design that embodied both the active pharmacophores in a single molecule in order to evaluate their synergic activity against a series of tumor cell lines [31], showing some of

Kamal et al. [32] also designed a novel series of imidazole merged with thiazole as chalcone-like derivatives and evaluated their cytotoxic activity against MCF-7, A549, HeLA, DU-145, and HT-29 cell lines. Among the compounds tested, structure **13** (**Figure 4**) with a pyridyl ring was the most active. This compound also disrupted microtubule dynamics, induced cell cycle arrest in G2/M phase and

**Pyrimidines**: Compounds with fused rings can also be formed by merging other

heterocyclic moieties with thiazole core. Li et al. [33] reported a novel series of thiazolo[5,4-*d*]pyrimidine derivatives, which were evaluated against three cancer cell lines. Compound **14** (**Figure 4**) showed the most potent antiproliferative activity with good selectivity when compared to normal cells (IC50 values of 1.03 μM against MGC803 and 38.95 μM against GES-1). Biological studies indicated that this compound could inhibit the cell colony formation and migration by inducing

A series of thiazolo[3,2-*a*]pyrimidines were synthetized and evaluated in the NCI-60 cell lines panel assay, achieving significant cytotoxicity against some of the

**Diazepines**: Heterocyclic compounds 1,4-diazepines are considered an interesting moiety in drug research due to their broad range of pharmacological activities, including antibacterial, anti-HIV, anticonvulsant, and anticancer [35]. Ramírez et al. designed a series of novel thiazole-based compounds by fusing this structure with pyrimidine, which has also showed biological properties. The results indicated that some compounds showed promising antitumoral activity, with GI50 values

**Pyrazoline**: Another heterocyclic structure used in combination with thiazole moiety is the pyrazoline ring. New thiazolyl-pyrazoline derivatives were synthetized, and their cytotoxicity was evaluated against A549 human lung adenocarcinoma and NIH/3 T3 mouse embryonic fibroblast cells, presenting in some cases

**Curcumins**: Bayomi et al. [37] synthetized and evaluated a series of new curcumin analogs bearing thiazole as antitumoral and antioxidant agents, showing

**Thiazolines**: Thiazolines are the reduced form of thiazole and also have attracted interest in drug research due to its biological activity. Altintop et al. [38] evaluated a series of new thiazoline-based derivatives bearing a hydrazone moiety. The results showed that some of the compounds were potent inhibitors of DNA

There is a great variability of transition metals that in combination with different ligands have been reported as antitumoral agents acting through different mechanisms. The literature revealed the considerable interest in the thiazole

similar behavior than that of cisplatin and ascorbic acid, respectively.

**4. Miscellaneous structures bearing thiazole ring**

below 2 μM against NCI's *in vitro* cell line screening [35].

similar IC50 values to cisplatin [36].

synthesis against C6 tumor cells.

**5. Thiazole and metal complexes**

**62**

related to different functional groups on TTDC and RDPA ligands. Owing to the presence of sulfur and amino groups in CuTTDC and CuRDPA, these complexes had emerged as ligands to attach to delivery vehicles, such as peptides or monoclonal antibodies for targeted delivery.

It is notably that a number of copper (II) complexes have been shown to present antitumor activity, through inhibition of human topoisomerase IIα. Recently, Sandhaus et al*.* [47] have identified a new complex (compound **16** in **Figure 5**) with potent antiproliferative activity towards colon cancer cell lines (HTC-116, Caco-2, and HT-29) and aggressive breast cancer cell lines (HCC 1500, HCC 70, HCC 1806, and HCC 1395).

**Ruthenium complexes**: Currently, ruthenium complexes are found to be a promising alternative for platinum because of favorable properties as anticancer drugs. Among the ligands, 2,6-di(thiazol-2-yl)pyridine combined with phenantrolines have demonstrated to act as DNA intercalative agents along with topoisomerase I and IIα inhibitors (compound **17** in **Figure 5**) [48]. The assays with other ligands, such as 1,3-thiazolidine-2-thione, with 1,4-bis(diphenylphosphino)butane or 2,2′-bipyridine, displayed strong cytotoxicity against breast and prostate cancer cell lines [49].

**Platinum and palladium complexes**: Platinum and palladium have similar chemical properties and modes of coordination, but the palladium compounds are more labile from a thermodynamic and a kinetic point of view with relation to platinum derivatives.

Rubino and co-workers [50] have reported two new mono-Pt(II) and binuclear chloro-bridged Pd(II) complexes with 2,2′-dithiobis(benzothiazole) as ligand. Only platinum derivative has emerged as an effective inductor of apoptotic death on HepG2 and MCF-7 cells and caused cell cycle arrest at G0/G1 phase while palladium was inactive. On the other hand, the inclusion of 2-(4-substituted)benzothiazoles (compound **18** in **Figure 5**) as ligands resulted in potent cytotoxic agents through tubulin polymerization in A549 and HeLa cell lines [51].

In addition, thiazolidinone-derived complexes, specifically with (*Z*)-2-((*E*)-(1- (pyridin-2-yl)ethylidene)hydrazono)thiazolidin-4-one, were markedly cytotoxic to MCF-7, HepG2, and NCI-H460 and presented better profile than cisplatin [52]. Other relevant strategy is the combination with scaffold with proven anticancer activity. In this context, the coumarin-thiazole analogs complexed with platinum or palladium showed that the Pd complex had higher antitumor effects than its Pt analogs in several cancer cell lines [53].

**Other metal complexes and applications**: Manganese is a metal that plays a critical role in cell development, and it is required for mitochondrial function. As novelty, Islam et al*.* [54] have described a new Mn-EDTA complex (compound **19** in **Figure 5**) incorporating a benzothiazole that has been investigated as potential agents for diagnosis of liver cancer by magnetic resonance.

Cobalt (II) complexes are one of the most studied, and they have been reported as cytotoxic agents *in vitro* against breast cancer cell lines [55]. However, the cobalt (III) complexes are less known, although a new Co(III)sulfathiazole complex have been reported as cytotoxic compound without genotoxic effects [56].

In recent years, lanthanum (III) complexes are emerging as promising agents due to their more physiological activities and lower toxicities after coordination with ligands. The main mechanism of action associated is the interaction with DNA by intercalation mode. Likewise, these compounds are useful as clinical biomarkers for early diagnosis of the presence of prostate cancer. One of the most relevant lanthanum (III) derivative is 2,3-dihydro-1*H*-indolo[2,3-*b*]phenazin-4-(5*H*) ylidene)benzothiazole-2-amine (compound **20** in **Figure 5**) that showed excellent anticancer activity in PC-3 cells [57].

**65**

*Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds*

Another relevant option is the gold(I) compounds that can act as prodrugs. Thus, 2-mercapto thiazoline as ligand by reaction with K[Au(CN)2] resulted in the nitrogen-coordinated complex [NCAu(N-mtz)]. On the other hand, reaction with [(Ph3P)AuCl] yielded the sulfur-coordinated complex [(Ph3P)Au(S-mtz)]. Both of them inhibited the growth of tumorigenic cell lines such as the human ovarian carcinoma (A2780), human colon carcinoma (HCT116), and human breast adeno-

Finally, another strategy to design new complexes as antitumoral agents is the combination of anti-inflammatory derivatives with metals. In this approach, the 1,2-benzothiazines nuclei, which are present in meloxicam and piroxicam, were complexed with ruthenium and osmium to obtain new derivatives with potent

Thiazoles and thiazolines are quite common motifs present in peptides isolated from natural sources, many of them known for having biological activity, typically antibacterial. These peptides are biosynthesized from nonribosomal peptide synthase (NRPS) or ribosomally produced and post-translationally modified. Both processes involve cyclodehydrations of cysteine residues to yield thiazolines and subsequent dehydrogenations to give thiazoles [60]. In this context, marine organism (cyanobacteria, fungi, sponges, tunicates, ascidians, etc.) provide an endless source of new structures with biological potential, cancer included [61]. Many isolated thiazole-containing peptides from nature have anticancer properties *per se*, but more efforts are continuously needed by scientific community to enhance and modulate its anticancer activity through structure modifications. Recent develop-

Cyanobacteria-derived bisebromoamide was isolated and tested against HeLa S3 cells, showing a very low IC50 [62]. It was also shown to induce apoptosis through ERK and mTOR inhibition in renal carcinoma cell lines [63]. A modification of central thiazoline of bisebromoamide by a thiazole and alanine scanning [64] provided new analogs, getting insights in the structural dependence of the cytotoxicity. Four analogs showed nanomolar cytotoxicity activity against human colon tumor cell

P-glycoprotein (P-gp, multidrug resistance protein 1) is overexpressed in patients suffering from chemotherapy resistance. In this sense, cyclic and acyclic (*S*)-valine-derived thiazole peptide dimers, trimers, and tetramers were found to be potent P-gp efflux transport inhibitors [65]. Based on this hit, further derivatization led to peptidomimetic TTT-28 (**Figure 6**), which was found to be a potent P-gp transport inhibitor and superior to parent compound in reversal of resistance to placitaxel in SW620/Ad300 and HEK/ABCB1 cell lines [66]. *In vivo* study [67] showed TTT-28 enhanced intratumoral concentration of placitaxel, inhibiting the growth of ABCB1 overexpressing tumors. Additional extensive derivatizations of TTT-28 in terminal groups and central thiazole building block side chain helped to understand the drug/substrate interactions with P-gp [68]. Modifications on these sites led to divergent effects in ATPase efflux pump, from initial stimulation in

Polyamides based on 2 and 3 repeating units of 2-aminothiazole-4-carboxylic acid were synthetized [69] and proved to bind selectively to c-*MYC* quadruplex

ments in this area are included here and listed by its cyclic/acyclic nature.

*DOI: http://dx.doi.org/10.5772/intechopen.82741*

carcinoma (MCF7) [58].

**6. Peptidic thiazoles**

**6.1 Linear peptides**

line HCT116.

TTT-28 to inhibition.

activity against cancer cell lines [59].

*Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds DOI: http://dx.doi.org/10.5772/intechopen.82741*

Another relevant option is the gold(I) compounds that can act as prodrugs. Thus, 2-mercapto thiazoline as ligand by reaction with K[Au(CN)2] resulted in the nitrogen-coordinated complex [NCAu(N-mtz)]. On the other hand, reaction with [(Ph3P)AuCl] yielded the sulfur-coordinated complex [(Ph3P)Au(S-mtz)]. Both of them inhibited the growth of tumorigenic cell lines such as the human ovarian carcinoma (A2780), human colon carcinoma (HCT116), and human breast adenocarcinoma (MCF7) [58].

Finally, another strategy to design new complexes as antitumoral agents is the combination of anti-inflammatory derivatives with metals. In this approach, the 1,2-benzothiazines nuclei, which are present in meloxicam and piroxicam, were complexed with ruthenium and osmium to obtain new derivatives with potent activity against cancer cell lines [59].

#### **6. Peptidic thiazoles**

*Heterocycles - Synthesis and Biological Activities*

nal antibodies for targeted delivery.

and HCC 1395).

cell lines [49].

platinum derivatives.

related to different functional groups on TTDC and RDPA ligands. Owing to the presence of sulfur and amino groups in CuTTDC and CuRDPA, these complexes had emerged as ligands to attach to delivery vehicles, such as peptides or monoclo-

It is notably that a number of copper (II) complexes have been shown to present antitumor activity, through inhibition of human topoisomerase IIα. Recently, Sandhaus et al*.* [47] have identified a new complex (compound **16** in **Figure 5**) with potent antiproliferative activity towards colon cancer cell lines (HTC-116, Caco-2, and HT-29) and aggressive breast cancer cell lines (HCC 1500, HCC 70, HCC 1806,

**Ruthenium complexes**: Currently, ruthenium complexes are found to be a promising alternative for platinum because of favorable properties as anticancer drugs. Among the ligands, 2,6-di(thiazol-2-yl)pyridine combined with phenantrolines have demonstrated to act as DNA intercalative agents along with topoisomerase I and IIα inhibitors (compound **17** in **Figure 5**) [48]. The assays with other ligands, such as 1,3-thiazolidine-2-thione, with 1,4-bis(diphenylphosphino)butane or 2,2′-bipyridine, displayed strong cytotoxicity against breast and prostate cancer

**Platinum and palladium complexes**: Platinum and palladium have similar chemical properties and modes of coordination, but the palladium compounds are more labile from a thermodynamic and a kinetic point of view with relation to

Rubino and co-workers [50] have reported two new mono-Pt(II) and binuclear chloro-bridged Pd(II) complexes with 2,2′-dithiobis(benzothiazole) as ligand. Only platinum derivative has emerged as an effective inductor of apoptotic death on HepG2 and MCF-7 cells and caused cell cycle arrest at G0/G1 phase while palladium was inactive. On the other hand, the inclusion of 2-(4-substituted)benzothiazoles (compound **18** in **Figure 5**) as ligands resulted in potent cytotoxic agents through

In addition, thiazolidinone-derived complexes, specifically with (*Z*)-2-((*E*)-(1- (pyridin-2-yl)ethylidene)hydrazono)thiazolidin-4-one, were markedly cytotoxic to MCF-7, HepG2, and NCI-H460 and presented better profile than cisplatin [52]. Other relevant strategy is the combination with scaffold with proven anticancer activity. In this context, the coumarin-thiazole analogs complexed with platinum or palladium showed that the Pd complex had higher antitumor effects than its Pt

**Other metal complexes and applications**: Manganese is a metal that plays a critical role in cell development, and it is required for mitochondrial function. As novelty, Islam et al*.* [54] have described a new Mn-EDTA complex (compound **19** in **Figure 5**) incorporating a benzothiazole that has been investigated as potential

Cobalt (II) complexes are one of the most studied, and they have been reported as cytotoxic agents *in vitro* against breast cancer cell lines [55]. However, the cobalt (III) complexes are less known, although a new Co(III)sulfathiazole complex have

In recent years, lanthanum (III) complexes are emerging as promising agents due to their more physiological activities and lower toxicities after coordination with ligands. The main mechanism of action associated is the interaction with DNA by intercalation mode. Likewise, these compounds are useful as clinical biomarkers for early diagnosis of the presence of prostate cancer. One of the most relevant lanthanum (III) derivative is 2,3-dihydro-1*H*-indolo[2,3-*b*]phenazin-4-(5*H*) ylidene)benzothiazole-2-amine (compound **20** in **Figure 5**) that showed excellent

tubulin polymerization in A549 and HeLa cell lines [51].

agents for diagnosis of liver cancer by magnetic resonance.

been reported as cytotoxic compound without genotoxic effects [56].

analogs in several cancer cell lines [53].

anticancer activity in PC-3 cells [57].

**64**

Thiazoles and thiazolines are quite common motifs present in peptides isolated from natural sources, many of them known for having biological activity, typically antibacterial. These peptides are biosynthesized from nonribosomal peptide synthase (NRPS) or ribosomally produced and post-translationally modified. Both processes involve cyclodehydrations of cysteine residues to yield thiazolines and subsequent dehydrogenations to give thiazoles [60]. In this context, marine organism (cyanobacteria, fungi, sponges, tunicates, ascidians, etc.) provide an endless source of new structures with biological potential, cancer included [61]. Many isolated thiazole-containing peptides from nature have anticancer properties *per se*, but more efforts are continuously needed by scientific community to enhance and modulate its anticancer activity through structure modifications. Recent developments in this area are included here and listed by its cyclic/acyclic nature.

#### **6.1 Linear peptides**

Cyanobacteria-derived bisebromoamide was isolated and tested against HeLa S3 cells, showing a very low IC50 [62]. It was also shown to induce apoptosis through ERK and mTOR inhibition in renal carcinoma cell lines [63]. A modification of central thiazoline of bisebromoamide by a thiazole and alanine scanning [64] provided new analogs, getting insights in the structural dependence of the cytotoxicity. Four analogs showed nanomolar cytotoxicity activity against human colon tumor cell line HCT116.

P-glycoprotein (P-gp, multidrug resistance protein 1) is overexpressed in patients suffering from chemotherapy resistance. In this sense, cyclic and acyclic (*S*)-valine-derived thiazole peptide dimers, trimers, and tetramers were found to be potent P-gp efflux transport inhibitors [65]. Based on this hit, further derivatization led to peptidomimetic TTT-28 (**Figure 6**), which was found to be a potent P-gp transport inhibitor and superior to parent compound in reversal of resistance to placitaxel in SW620/Ad300 and HEK/ABCB1 cell lines [66]. *In vivo* study [67] showed TTT-28 enhanced intratumoral concentration of placitaxel, inhibiting the growth of ABCB1 overexpressing tumors. Additional extensive derivatizations of TTT-28 in terminal groups and central thiazole building block side chain helped to understand the drug/substrate interactions with P-gp [68]. Modifications on these sites led to divergent effects in ATPase efflux pump, from initial stimulation in TTT-28 to inhibition.

Polyamides based on 2 and 3 repeating units of 2-aminothiazole-4-carboxylic acid were synthetized [69] and proved to bind selectively to c-*MYC* quadruplex

#### **Figure 6.**

*Thiazole/thiazoline containing peptides and peptidomimetics with anticancer activity.*

over other G-quadruplex and duplex DNA and therefore inhibiting c-*MYC* oncogene transcription. Antiproliferative activity of the tripeptide was found in HeLa cells, caused by apoptotic pathway.

Thiazole scaffold is also present in short peptides known for inhibiting tubulin polymerization. Dolastatin 10 was firstly isolated from *Dolabella auricularia* and is composed of five unnatural amino acids with a thiazole ring in C-terminal (**Figure 6**). It was demonstrated as very potent in cell proliferation assays (IC50 < 5.0 nM), but due to its high toxicity at maximum tolerated dose, new analogs have been developed. *N*-Terminal modified dolastatin analog (PF-06380101) bearing a quaternary amino acid was found to have improved potency and suitable ADME properties for antibody-drug conjugates [70]. Modified dolastatins at thiazole moiety by addition of new functionalities as alcohols, amines, and thiols have also been reported [71]. These analogs also showed low IC50 for several cancerous cell lines.

Another thiazole-containing peptides targeting to tubulin polymerization are the tubulysins (**Figure 6**), isolated first from myxobacteria. Great number of modifications have been attempted to date, and numerous SAR studies have shed light into tubulysin mode of action (for a review, see ref. [72]).

In this context, a pretubulysin (tubulysin biosynthetic precursors) lacking of *C*<sup>11</sup> acetate and bearing a methyl group at *N*14 showed efficacy against various *in vivo* metastatic bladder, breast, and lung cancer models [73]. New tubulysin derivative KEMTUB10 with a *N*14-benzyl-Tuv and 4-fluorophenyl moiety in Tup exhibited activity in the picomolar range in the main breast cancer cell lines [74]. It blocks cells in G2/M phase of the cell cycle and stimulates apoptosis. In line with these results, attachment of alkyl groups at mentioned Tuv *N*14 as benzyl, 4 fluorobenzyl, and cyclopropylmethyl in tubulysins also led to superpotent cytotoxic activity [75]. More Tuv modifications have been reported, like the incorporation of tetrahydropyranyl ring by Diels-Alder reaction for conformational restriction of tubulysin [76], but rigidification seemed to affect negatively to polymerization inhibition. Systematic derivatization by substitution of each subunit of tubulysin by diverse moieties, including three-dimensional structural motifs such as cubane and [1.1.1]-bicyclopentane, was reported [77]. A profound structure-activity study indicated that thiazole in Tuv unit cannot be substituted by 3D motifs but can be replaced by aromatics such as pyridine without significant loss of activity.

**67**

*Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds*

One objective for researchers working with tubulysins is the improvement of their therapeutic efficacy by the targeted cancer therapy as antibody-drug conjugation (ADC) or small molecule drug conjugates (SMDC), acting the tubulysins as payloads. This represents a very powerful tool, which is already being applied to all class of tubulin inhibitors [78]. Tubulysin warheads are therefore being used in ADC; one of them (AZ13599185) is in phase I clinical trials targeting HER2 receptors, involved in breast cancer development [79]. Following this trend, the modifications of tubulysins for an easier linking to conjugates is a new goal. New derivatizations at *C*-terminal Tup showed broad tolerance with no loss of activity, enabling more opportunities to conjugate to biomolecules and receptor ligands [80]. Another issue that arose during ADC conjugation of tubulysins to trastuzumab is the metabolism of *C*11 acetate *in vivo*, inactivating the payload [81, 82]. The problem was solved replacing the acetate ester by a more inert functionality to esterases like carbamates, retaining the activity. Tubulysin warheads have also been applied in a SMDC strategy in conjugation with folic acid to address folate receptor (FR), expressed in many cancers [83]. The EC1456 conjugate was tested in mice bearing FR-positive xenografts leading to curation of 100%. Results against human

Cyclic depsipeptide largazole was discovered from cyanobacteria *Symploca* sp. [84], and its distinctive structural feature is the presence of a thiazole fused linearly to a 4-methylthiazoline and a labile thioester (**Figure 6**). Largazole possesses great activity as inhibitor of class I histone deacetylase (HDAC) metalloenzymes [85], a promising target for chemotherapy. Many largazole structure-activity relationship studies have been reported. Among multiple sites of modification performed, thiazole-thiazoline fragment located in the macrocycle seems to be the most promising to achieve more potent and selective analogues. Substitution of thiazole by pyridyl residues and depsipeptide framework alteration to peptide isostere led to equipotent largazole analogues but with improved selectivity for different HDACs [86]. The replacement of thiazole and thiazoline by bipyridyl fragments led to derivatives with a similar activity of largazole, but with an improved selectivity for

Largazole inhibition of HDAC is actually attained by largazole thiol derived from thioester hydrolysis. The thiol forms a thiolate-Zn2+ complex [88], a critical binding for the activity, since substitution by other poorer Zn-binding groups correlated to less HDAC inhibition and lower cytotoxicity [89]. The octanoyl side chain on the thioester allows good cell permeability. Thus, modifications can be made for a better membrane permeability and thiol liberation inside the cell. In this sense, controlled release of largazole thiol from an isobutylene-caged largazole thiol derivative, which possesses a high permeability, has been achieved by UV light

Cyclic thiazole- and oxazoline-containing octapeptides and patellamides, isolated from marine tunicates, have also been an object of modification. It has been shown that changes in the position of thiazoles and oxazolines in ascidiacyclamide can influence their cytotoxic activity, obtaining inactive derivatives and 10 times

Apratoxin- and thiazoline-containing depsipeptides are known potent cytotoxins isolated from marine cyanobacteria. Apratoxins are known for being potent anticancer agents and co-translational translocation inhibitors. Different derivatives have been synthetized, involving thiazoline stereogenic configuration change at *C*30 and substitution in *C*34 [92] (**Figure 6**). A new derivative, apratoxin S10 with

more active compounds depending on the conformations attained [91].

*DOI: http://dx.doi.org/10.5772/intechopen.82741*

vintafolide-resistant xenografts were also positive.

photoactivation of a thiol-ene triggering reaction [90].

**6.2 Cyclic peptides**

class I HDAC [87].

#### *Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds DOI: http://dx.doi.org/10.5772/intechopen.82741*

One objective for researchers working with tubulysins is the improvement of their therapeutic efficacy by the targeted cancer therapy as antibody-drug conjugation (ADC) or small molecule drug conjugates (SMDC), acting the tubulysins as payloads. This represents a very powerful tool, which is already being applied to all class of tubulin inhibitors [78]. Tubulysin warheads are therefore being used in ADC; one of them (AZ13599185) is in phase I clinical trials targeting HER2 receptors, involved in breast cancer development [79]. Following this trend, the modifications of tubulysins for an easier linking to conjugates is a new goal. New derivatizations at *C*-terminal Tup showed broad tolerance with no loss of activity, enabling more opportunities to conjugate to biomolecules and receptor ligands [80]. Another issue that arose during ADC conjugation of tubulysins to trastuzumab is the metabolism of *C*11 acetate *in vivo*, inactivating the payload [81, 82]. The problem was solved replacing the acetate ester by a more inert functionality to esterases like carbamates, retaining the activity. Tubulysin warheads have also been applied in a SMDC strategy in conjugation with folic acid to address folate receptor (FR), expressed in many cancers [83]. The EC1456 conjugate was tested in mice bearing FR-positive xenografts leading to curation of 100%. Results against human vintafolide-resistant xenografts were also positive.

#### **6.2 Cyclic peptides**

*Heterocycles - Synthesis and Biological Activities*

cells, caused by apoptotic pathway.

**Figure 6.**

over other G-quadruplex and duplex DNA and therefore inhibiting c-*MYC* oncogene transcription. Antiproliferative activity of the tripeptide was found in HeLa

Thiazole scaffold is also present in short peptides known for inhibiting tubulin polymerization. Dolastatin 10 was firstly isolated from *Dolabella auricularia* and is composed of five unnatural amino acids with a thiazole ring in C-terminal (**Figure 6**). It was demonstrated as very potent in cell proliferation assays (IC50 < 5.0 nM), but due to its high toxicity at maximum tolerated dose, new analogs have been developed. *N*-Terminal modified dolastatin analog (PF-06380101) bearing a quaternary amino acid was found to have improved potency and suitable ADME properties for antibody-drug conjugates [70]. Modified dolastatins at thiazole moiety by addition of new functionalities as alcohols, amines, and thiols have also been reported [71].

Another thiazole-containing peptides targeting to tubulin polymerization are the tubulysins (**Figure 6**), isolated first from myxobacteria. Great number of modifications have been attempted to date, and numerous SAR studies have shed

In this context, a pretubulysin (tubulysin biosynthetic precursors) lacking of *C*<sup>11</sup> acetate and bearing a methyl group at *N*14 showed efficacy against various *in vivo* metastatic bladder, breast, and lung cancer models [73]. New tubulysin derivative KEMTUB10 with a *N*14-benzyl-Tuv and 4-fluorophenyl moiety in Tup exhibited activity in the picomolar range in the main breast cancer cell lines [74]. It blocks cells in G2/M phase of the cell cycle and stimulates apoptosis. In line with these

fluorobenzyl, and cyclopropylmethyl in tubulysins also led to superpotent cytotoxic activity [75]. More Tuv modifications have been reported, like the incorporation of tetrahydropyranyl ring by Diels-Alder reaction for conformational restriction of tubulysin [76], but rigidification seemed to affect negatively to polymerization inhibition. Systematic derivatization by substitution of each subunit of tubulysin by diverse moieties, including three-dimensional structural motifs such as cubane and [1.1.1]-bicyclopentane, was reported [77]. A profound structure-activity study indicated that thiazole in Tuv unit cannot be substituted by 3D motifs but can be replaced by aromatics such as pyridine without significant loss of activity.

These analogs also showed low IC50 for several cancerous cell lines.

*Thiazole/thiazoline containing peptides and peptidomimetics with anticancer activity.*

light into tubulysin mode of action (for a review, see ref. [72]).

results, attachment of alkyl groups at mentioned Tuv *N*14 as benzyl, 4-

**66**

Cyclic depsipeptide largazole was discovered from cyanobacteria *Symploca* sp. [84], and its distinctive structural feature is the presence of a thiazole fused linearly to a 4-methylthiazoline and a labile thioester (**Figure 6**). Largazole possesses great activity as inhibitor of class I histone deacetylase (HDAC) metalloenzymes [85], a promising target for chemotherapy. Many largazole structure-activity relationship studies have been reported. Among multiple sites of modification performed, thiazole-thiazoline fragment located in the macrocycle seems to be the most promising to achieve more potent and selective analogues. Substitution of thiazole by pyridyl residues and depsipeptide framework alteration to peptide isostere led to equipotent largazole analogues but with improved selectivity for different HDACs [86]. The replacement of thiazole and thiazoline by bipyridyl fragments led to derivatives with a similar activity of largazole, but with an improved selectivity for class I HDAC [87].

Largazole inhibition of HDAC is actually attained by largazole thiol derived from thioester hydrolysis. The thiol forms a thiolate-Zn2+ complex [88], a critical binding for the activity, since substitution by other poorer Zn-binding groups correlated to less HDAC inhibition and lower cytotoxicity [89]. The octanoyl side chain on the thioester allows good cell permeability. Thus, modifications can be made for a better membrane permeability and thiol liberation inside the cell. In this sense, controlled release of largazole thiol from an isobutylene-caged largazole thiol derivative, which possesses a high permeability, has been achieved by UV light photoactivation of a thiol-ene triggering reaction [90].

Cyclic thiazole- and oxazoline-containing octapeptides and patellamides, isolated from marine tunicates, have also been an object of modification. It has been shown that changes in the position of thiazoles and oxazolines in ascidiacyclamide can influence their cytotoxic activity, obtaining inactive derivatives and 10 times more active compounds depending on the conformations attained [91].

Apratoxin- and thiazoline-containing depsipeptides are known potent cytotoxins isolated from marine cyanobacteria. Apratoxins are known for being potent anticancer agents and co-translational translocation inhibitors. Different derivatives have been synthetized, involving thiazoline stereogenic configuration change at *C*30 and substitution in *C*34 [92] (**Figure 6**). A new derivative, apratoxin S10 with (*R*)-*C*30 thiazoline and the addition of a methyl group at *C*34, shows potent *in vitro* angiogenesis and vascularized tumor cell growth inhibition [93]. It showed antipancreatic cancer activity, including in orthotopic pancreatic patient-derived xenograft mouse model [94]. Other derivatizations consisting of thiazoline substitution by piperidinecarboxylic acid moiety have been developed [95]. Apratoxins M16 showed comparable cytotoxicity to apratoxin A in HCT116 cancerous cells.

### **7. Conclusion**

Incorporation of thiazole ring into different molecules have demonstrated to be a novel and promising approach to design more potent and safer antitumor drugs. The results of this chapter might help to enlighten other researchers to better design bioactive molecules. This thiazole ring can be incorporated as part of mono- or fused-cycles, metal complexes, or as a part of peptides. In many of these cases, the deletion of thiazole ring entails the loss of the bioactivity pointing out the importance of this ring for the anticancer activity. Thus, we consider this class of compounds and excellent starting point to achieve future drug candidates to treat cancer.

### **Author details**

Sandra Ramos-Inza1,2, Carlos Aydillo1,2, Carmen Sanmartín1,2 and Daniel Plano1,2\*

1 Faculty of Pharmacy and Nutrition, Department of Pharmaceutical Technology and Chemistry, University of Navarra, Pamplona, Spain

2 Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

\*Address all correspondence to: dplano@alumni.unav.es

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**69**

*Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds*

of chalcones: A mini review. European Journal of Medicinal Chemistry. 2014;**85**:758-777. DOI: 10.1016/j.

[8] Ayati A, Esmaeili R, Moghimi S, Oghabi Bakhshaiesh T, Eslami SZ, Majidzadeh AK, et al. Synthesis and biological evaluation of 4-amino-5 cinnamoylthiazoles as chalcone-like anticancer agents. European Journal of Medicinal Chemistry. 2018;**145**:404-412. DOI: 10.1016/j.ejmech.2018.01.015

[9] Jashari A, Imeri F, Ballazhi L, Shabani A, Mikhova B, Drager G, et al. Synthesis and cellular

[10] Gali R, Banothu J, Gondru R, Bavantula R, Velivela Y, Crooks PA. Onepot multicomponent synthesis of indole incorporated thiazolylcoumarins and their antibacterial, anticancer and DNA cleavage studies. Bioorganic & Medicinal Chemistry Letters. 2015;**25**:106-112. DOI: 10.1016/j.

[11] Ayati A, Oghabi Bakhshaiesh T, Moghimi S, Esmaeili R, Majidzadeh AK, Safavi M, et al. Synthesis and biological evaluation of new coumarins bearing 2,4-diaminothiazole-5-carbonyl moiety. European Journal of Medicinal Chemistry. 2018;**155**:483-491. DOI: 10.1016/j.ejmech.2018.06.015

[12] Vasudevan S, Thomas SA, Sivakumar KC, Komalam RJ,

Sreerekha KV, Rajasekharan KN, et al. Diaminothiazoles evade multidrug resistance in cancer cells and xenograft tumour models and develop transient

bmc.2014.03.026

bmcl.2014.10.100

characterization of novel isoxazolo- and thiazolohydrazinylidene-chroman-2, 4-diones on cancer and non-cancer cell growth and death. Bioorganic & Medicinal Chemistry. 2014;**22**: 2655-2661. DOI: 10.1016/j.

ejmech.2014.08.033

*DOI: http://dx.doi.org/10.5772/intechopen.82741*

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2018;**68**:394-424. DOI:

[2] Das D, Sikdar P, Bairagi M. Recent developments of 2-aminothiazoles in medicinal chemistry. European Journal of Medicinal Chemistry. 2016;**109**:89-98. DOI: 10.1016/j.ejmech.2015.12.022

[3] Rostom SA, Faidallah HM, Radwan MF, Badr MH. Bifunctional ethyl 2-amino-4-methylthiazole-5 carboxylate derivatives: Synthesis and in vitro biological evaluation as antimicrobial and anticancer agents. European Journal of Medicinal Chemistry. 2014;**76**:170-181. DOI: 10.1016/j.ejmech.2014.02.027

[4] Sun M, Xu Q, Xu J, Wu Y, Wang Y, Zuo D, et al. Synthesis and bioevaluation of N,4-diaryl-1, 3-thiazole-2-amines as tubulin

inhibitors with potent antiproliferative activity. PLoS One. 2017;**12**:e0174006. DOI: 10.1371/journal.pone.0174006

[5] Lu H, Rogowskyj J, Yu W, Venkatesh A, Khan N, Nakagawa S, et al. Novel substituted aminothiazoles as potent and selective anti-hepatocellular carcinoma

[6] Schiedel M, Rumpf T, Karaman B, Lehotzky A, Olah J, Gerhardt S, et al. Aminothiazoles as potent and selective Sirt2 inhibitors: A structure-activity relationship study. Journal of Medicinal Chemistry. 2016;**59**:1599-1612. DOI: 10.1021/acs.jmedchem.5b01517

[7] Singh P, Anand A, Kumar V. Recent developments in biological activities

agents. Bioorganic & Medicinal Chemistry Letters. 2016;**26**:5819-5824. DOI: 10.1016/j.bmcl.2016.10.015

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10.3322/caac.21492

*Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds DOI: http://dx.doi.org/10.5772/intechopen.82741*

#### **References**

*Heterocycles - Synthesis and Biological Activities*

**68**

**Author details**

**7. Conclusion**

cancer.

provided the original work is properly cited.

and Chemistry, University of Navarra, Pamplona, Spain

\*Address all correspondence to: dplano@alumni.unav.es

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Sandra Ramos-Inza1,2, Carlos Aydillo1,2, Carmen Sanmartín1,2 and Daniel Plano1,2\*

(*R*)-*C*30 thiazoline and the addition of a methyl group at *C*34, shows potent *in vitro* angiogenesis and vascularized tumor cell growth inhibition [93]. It showed antipancreatic cancer activity, including in orthotopic pancreatic patient-derived xenograft mouse model [94]. Other derivatizations consisting of thiazoline substitution by piperidinecarboxylic acid moiety have been developed [95]. Apratoxins M16 showed comparable cytotoxicity to apratoxin A in HCT116 cancerous cells.

Incorporation of thiazole ring into different molecules have demonstrated to be a novel and promising approach to design more potent and safer antitumor drugs. The results of this chapter might help to enlighten other researchers to better design bioactive molecules. This thiazole ring can be incorporated as part of mono- or fused-cycles, metal complexes, or as a part of peptides. In many of these cases, the deletion of thiazole ring entails the loss of the bioactivity pointing out the importance of this ring for the anticancer activity. Thus, we consider this class of compounds and excellent starting point to achieve future drug candidates to treat

1 Faculty of Pharmacy and Nutrition, Department of Pharmaceutical Technology

2 Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2018;**68**:394-424. DOI: 10.3322/caac.21492

[2] Das D, Sikdar P, Bairagi M. Recent developments of 2-aminothiazoles in medicinal chemistry. European Journal of Medicinal Chemistry. 2016;**109**:89-98. DOI: 10.1016/j.ejmech.2015.12.022

[3] Rostom SA, Faidallah HM, Radwan MF, Badr MH. Bifunctional ethyl 2-amino-4-methylthiazole-5 carboxylate derivatives: Synthesis and in vitro biological evaluation as antimicrobial and anticancer agents. European Journal of Medicinal Chemistry. 2014;**76**:170-181. DOI: 10.1016/j.ejmech.2014.02.027

[4] Sun M, Xu Q, Xu J, Wu Y, Wang Y, Zuo D, et al. Synthesis and bioevaluation of N,4-diaryl-1, 3-thiazole-2-amines as tubulin inhibitors with potent antiproliferative activity. PLoS One. 2017;**12**:e0174006. DOI: 10.1371/journal.pone.0174006

[5] Lu H, Rogowskyj J, Yu W, Venkatesh A, Khan N, Nakagawa S, et al. Novel substituted aminothiazoles as potent and selective anti-hepatocellular carcinoma agents. Bioorganic & Medicinal Chemistry Letters. 2016;**26**:5819-5824. DOI: 10.1016/j.bmcl.2016.10.015

[6] Schiedel M, Rumpf T, Karaman B, Lehotzky A, Olah J, Gerhardt S, et al. Aminothiazoles as potent and selective Sirt2 inhibitors: A structure-activity relationship study. Journal of Medicinal Chemistry. 2016;**59**:1599-1612. DOI: 10.1021/acs.jmedchem.5b01517

[7] Singh P, Anand A, Kumar V. Recent developments in biological activities

of chalcones: A mini review. European Journal of Medicinal Chemistry. 2014;**85**:758-777. DOI: 10.1016/j. ejmech.2014.08.033

[8] Ayati A, Esmaeili R, Moghimi S, Oghabi Bakhshaiesh T, Eslami SZ, Majidzadeh AK, et al. Synthesis and biological evaluation of 4-amino-5 cinnamoylthiazoles as chalcone-like anticancer agents. European Journal of Medicinal Chemistry. 2018;**145**:404-412. DOI: 10.1016/j.ejmech.2018.01.015

[9] Jashari A, Imeri F, Ballazhi L, Shabani A, Mikhova B, Drager G, et al. Synthesis and cellular characterization of novel isoxazolo- and thiazolohydrazinylidene-chroman-2, 4-diones on cancer and non-cancer cell growth and death. Bioorganic & Medicinal Chemistry. 2014;**22**: 2655-2661. DOI: 10.1016/j. bmc.2014.03.026

[10] Gali R, Banothu J, Gondru R, Bavantula R, Velivela Y, Crooks PA. Onepot multicomponent synthesis of indole incorporated thiazolylcoumarins and their antibacterial, anticancer and DNA cleavage studies. Bioorganic & Medicinal Chemistry Letters. 2015;**25**:106-112. DOI: 10.1016/j. bmcl.2014.10.100

[11] Ayati A, Oghabi Bakhshaiesh T, Moghimi S, Esmaeili R, Majidzadeh AK, Safavi M, et al. Synthesis and biological evaluation of new coumarins bearing 2,4-diaminothiazole-5-carbonyl moiety. European Journal of Medicinal Chemistry. 2018;**155**:483-491. DOI: 10.1016/j.ejmech.2018.06.015

[12] Vasudevan S, Thomas SA, Sivakumar KC, Komalam RJ, Sreerekha KV, Rajasekharan KN, et al. Diaminothiazoles evade multidrug resistance in cancer cells and xenograft tumour models and develop transient

specific resistance: Understanding the basis of broad-spectrum versus specific resistance. Carcinogenesis. 2015;**36**: 883-893. DOI: 10.1093/carcin/bgv072

[13] Thamkachy R, Kumar R, Rajasekharan KN, Sengupta S. ERK mediated upregulation of death receptor 5 overcomes the lack of p53 functionality in the diaminothiazole DAT1 induced apoptosis in colon cancer models: Efficiency of DAT1 in Ras-Raf mutated cells. Molecular Cancer. 2016;**15**:22. DOI: 10.1186/ s12943-016-0505-7

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[63] Suzuki K, Mizuno R, Suenaga K, Teruya T, Tanaka N, Kosaka T, et al. Bisebromoamide, an extract from Lyngbya species, induces apoptosis through ERK and mTOR inhibitions

in renal cancer cells. Cancer Medicine. 2013;**2**:32-39. DOI: 10.1002/cam4.53

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10.1021/acs.joc.6b01314

chem.201700874

bmc.2015.10.003

jacs.5b12557

molecules22081281

*DOI: http://dx.doi.org/10.5772/intechopen.82741*

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10.1093/nar/gky385

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[72] Murray BC, Peterson MT, Fecik RA. Chemistry and biology of tubulysins: Antimitotic tetrapeptides with activity against drug resistant cancers. Natural Product Reports. 2015;**32**:654-662. DOI: 10.1039/

[73] Braig S, Wiedmann RM, Liebl J, Singer M, Kubisch R, Schreiner L, et al. Pretubulysin: A new option for the treatment of metastatic cancer. Cell Death & Disease. 2014;**5**:e1001. DOI:

[74] Lamidi OF, Sani M, Lazzari P, Zanda M, Fleming IN. The tubulysin analogue KEMTUB10 induces apoptosis in breast cancer cells via p53, Bim and Bcl-2. Journal of Cancer Research and

[75] Sani M, Lazzari P, Folini M, Spiga M, Zuco V, De Cesare M, et al. Synthesis and Superpotent anticancer activity of tubulysins carrying non-hydrolysable

Clinical Oncology. 2015;**141**: 1575-1583. DOI: 10.1007/ s00432-015-1921-6

10.1016/j.bmc.2018.02.011

c4np00036f

10.1038/cddis.2013.510

*Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds DOI: http://dx.doi.org/10.5772/intechopen.82741*

[69] Dutta D, Debnath M, Müller D, Paul R, Das T, Bessi I, et al. Cell penetrating thiazole peptides inhibit c-MYC expression via site-specific targeting of c-MYC G-quadruplex. Nucleic Acids Research. 2018;**46**:5355-5365. DOI: 10.1093/nar/gky385

*Heterocycles - Synthesis and Biological Activities*

Spectrochimica Acta. Part A, Molecular

in renal cancer cells. Cancer Medicine. 2013;**2**:32-39. DOI: 10.1002/cam4.53

[64] Johnston HJ, Boys SK, Makda A, Carragher NO, Hulme AN. Naturally inspired peptide leads: Alanine scanning reveals an actin-targeting thiazole analogue of bisebromoamide. Chembiochem. 2016;**17**:1621-1627. DOI:

[65] Singh S, Prasad NR, Kapoor K, Chufan EE, Patel BA, Ambudkar SV, et al. Design, synthesis, and biological evaluation of ( S )-Valine Thiazole-derived cyclic and noncyclic

modulators of human P-glycoprotein (ABCB1). Chembiochem. 2014;**15**:157-169.

[66] Singh S, Prasad NR, Chufan EE, Patel BA, Wang YJ, Chen ZS, et al. Design and synthesis of human ABCB1 (P-glycoprotein) inhibitors by peptide coupling of diverse chemical scaffolds on carboxyl and amino termini of (S)-valine-derived thiazole amino acid. Journal of Medicinal Chemistry. 2014;**57**:4058-4072. DOI: 10.1021/

[67] Wang Y-J, Patel BA, Anreddy N, Zhang Y-K, Zhang G-N, Alqahtani S, et al. Thiazole-valine peptidomimetic (TTT-28) antagonizes multidrug resistance in vitro and in vivo by selectively inhibiting the efflux activity of ABCB1. Scientific

Reports. 2017;**7**:42106. DOI: 10.1038/

[68] Patel BA, Abel B, Barbuti AM, Velagapudi UK, Chen Z-S, Ambudkar SV, et al. Comprehensive synthesis of amino acid-derived Thiazole Peptidomimetic analogues to understand the enigmatic drug/ substrate-binding site of P-glycoprotein.

Journal of Medicinal Chemistry. 2018:61. DOI: 834-864. DOI: 10.1021/

acs.jmedchem.7b01340

peptidomimetic oligomers as

DOI: 10.1002/cbic.201300565

jm401966m

srep42106

10.1002/cbic.201600257

[58] Abbehausen C, Manzano CM, Corbi PP, Farrell NP. Effects of coordination mode of 2-mercaptothiazoline on reactivity of Au(I) compounds with thiols and sulfur-containing proteins. Journal of Inorganic Biochemistry. 2016;**165**:136-145. DOI: 10.1016/j.

and Biomolecular Spectroscopy. 2016;**155**:146-154. DOI: 10.1016/j.

saa.2015.10.015

jinorgbio.2016.05.011

10.1002/chem.201700263

R110.135970

10.3390/ijms19030919

DOI: 10.1021/ol9020546

[59] Aman F, Hanif M, Kubanik M, Ashraf A, Sohnel T, Jamieson SM, et al. Anti-inflammatory oxicams as multi-donor ligand systems: pH- and solvent-dependent coordination modes of meloxicam and piroxicam to Ru and Os. Chemistry. 2017;**23**:4893-4902. DOI:

[60] Walsh CT, Acker MG, Bowers AA. Thiazolyl peptide antibiotic biosynthesis: A cascade of posttranslational modifications on ribosomal nascent proteins. The Journal of Biological Chemistry.

2010;**285**:27525-27531. DOI: 10.1074/jbc.

[61] Kang H, Choi M-C, Seo C, Park Y. Therapeutic properties and biological benefits of marine-derived anticancer peptides. International Journal of Molecular Sciences. 2018;**19**:919. DOI:

[62] Teruya T, Sasaki H, Fukazawa H, Suenaga K. Bisebromoamide, a potent cytotoxic peptide from the marine *Cyanobacterium lyngbya* sp.: Isolation, stereostructure, and biological activity. Organic Letters. 2009;**11**:5062-5065.

[63] Suzuki K, Mizuno R, Suenaga K, Teruya T, Tanaka N, Kosaka T, et al. Bisebromoamide, an extract from Lyngbya species, induces apoptosis through ERK and mTOR inhibitions

**74**

[70] Maderna A, Doroski M, Subramanyam C, Porte A, Leverett CA, Vetelino BC, et al. Discovery of cytotoxic Dolastatin 10 analogues with N-terminal modifications. Journal of Medicinal Chemistry. 2014;**57**: 10527-10543. DOI: 10.1021/jm501649k

[71] Yokosaka S, Izawa A, Sakai C, Sakurada E, Morita Y, Nishio Y. Synthesis and evaluation of novel dolastatin 10 derivatives for versatile conjugations. Bioorganic & Medicinal Chemistry. 2018;**26**:1643-1652. DOI: 10.1016/j.bmc.2018.02.011

[72] Murray BC, Peterson MT, Fecik RA. Chemistry and biology of tubulysins: Antimitotic tetrapeptides with activity against drug resistant cancers. Natural Product Reports. 2015;**32**:654-662. DOI: 10.1039/ c4np00036f

[73] Braig S, Wiedmann RM, Liebl J, Singer M, Kubisch R, Schreiner L, et al. Pretubulysin: A new option for the treatment of metastatic cancer. Cell Death & Disease. 2014;**5**:e1001. DOI: 10.1038/cddis.2013.510

[74] Lamidi OF, Sani M, Lazzari P, Zanda M, Fleming IN. The tubulysin analogue KEMTUB10 induces apoptosis in breast cancer cells via p53, Bim and Bcl-2. Journal of Cancer Research and Clinical Oncology. 2015;**141**: 1575-1583. DOI: 10.1007/ s00432-015-1921-6

[75] Sani M, Lazzari P, Folini M, Spiga M, Zuco V, De Cesare M, et al. Synthesis and Superpotent anticancer activity of tubulysins carrying non-hydrolysable

N-substituents on tubuvaline. Chemistry - A European Journal. 2017;**23**:5842-5850. DOI: 10.1002/ chem.201700874

[76] Park Y, Bae SY, Hah J-M, Lee SK, Ryu J-S. Synthesis of stereochemically diverse cyclic analogs of tubulysins. Bioorganic & Medicinal Chemistry. 2015;**23**:6827-6843. DOI: 10.1016/j. bmc.2015.10.003

[77] Nicolaou KC, Yin J, Mandal D, Erande RD, Klahn P, Jin M, et al. Total synthesis and biological evaluation of natural and designed tubulysins. Journal of the American Chemical Society. 2016;**138**:1698-1708. DOI: 10.1021/ jacs.5b12557

[78] Chen H, Lin Z, Arnst K, Miller D, Li W. Tubulin inhibitor-based antibodydrug conjugates for cancer therapy. Molecules. 2017;**22**:1281. DOI: 10.3390/ molecules22081281

[79] Li JY, Perry SR, Muniz-Medina V, Wang X, Wetzel LK, Rebelatto MC, et al. A Biparatopic HER2-targeting antibody-drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. Cancer Cell. 2016;**29**:117-129. DOI: 10.1016/j.ccell.2015.12.008

[80] Colombo R, Wang Z, Han J, Balachandran R, Daghestani HN, Camarco DP, et al. Total synthesis and biological evaluation of tubulysin analogues. The Journal of Organic Chemistry. 2016;**81**:10302-10320. DOI: 10.1021/acs.joc.6b01314

[81] Leverett CA, Sukuru SCK, Vetelino BC, Musto S, Parris K, Pandit J, et al. Design, synthesis, and cytotoxic evaluation of novel tubulysin analogues as ADC payloads. ACS Medicinal Chemistry Letters. 2016;**7**:999-1004. DOI: 10.1021/ acsmedchemlett.6b00274

[82] Tumey N, Leverett CA, Vetelino B, Li F, Rago B, Han X, et al. Optimization of tubulysin antibody-drug conjugates: A case study in addressing ADC metabolism. ACS Medicinal Chemistry Letters. 2016;**7**:977-982. DOI: 10.1021/ acsmedchemlett.6b00195

[83] Reddy JA, Dorton R, Bloomfield A, Nelson M, Dircksen C, Vetzel M, et al. Pre-clinical evaluation of EC1456, a folate-tubulysin anti-cancer therapeutic. Scientific Reports. 2018;**8**:8943-8943. DOI: 10.1038/s41598-018-27320-5

[84] Ying Y, Taori K, Kim H, Hong J, Luesch H. Total synthesis and molecular target of largazole, a histone deacetylase inhibitor. Journal of the American Chemical Society. 2008;**130**:8455-8459. DOI: 10.1021/ja8013727

[85] Poli G, Di Fabio R, Ferrante L, Summa V, Botta M. Largazole analogues as histone deacetylase inhibitors and anticancer agents: An overview of structure-activity relationships. ChemMedChem. 2017;**12**:1917-1926. DOI: 10.1002/cmdc.201700563

[86] Clausen DJ, Smith WB, Haines BE, Wiest O, Bradner JE, Williams RM. Modular synthesis and biological activity of pyridyl-based analogs of the potent class I histone deacetylase inhibitor Largazole. Bioorganic & Medicinal Chemistry. 2015;**23**:5061-5074. DOI: 10.1016/j.bmc.2015.03.063

[87] Almaliti J, Al-Hamashi AA, Negmeldin AT, Hanigan CL, Perera L, Pflum MKH, et al. Largazole analogues embodying radical changes in the depsipeptide ring: Development of a more selective and highly potent analogue. Journal of Medicinal Chemistry. 2016;**59**:10642-10660. DOI: 10.1021/acs.jmedchem.6b01271

[88] Cole KE, Dowling DP, Boone MA, Phillips AJ, Christianson DW. Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases. Journal of the American Chemical Society. 2011;**133**:12474-12477. DOI: 10.1021/ja205972n

[89] Kim B, Ratnayake R, Lee H, Shi G, Zeller SL, Li C, et al. Synthesis and biological evaluation of largazole zincbinding group analogs. Bioorganic & Medicinal Chemistry. 2017;**25**:3077-3086. DOI: 10.1016/j.bmc.2017.03.071

[90] Sun S, Oliveira B, Jiménez-Osés G, Bernardes GJL. Radical-mediated thiol-ene strategy for photoactivation of thiol-containing drugs in cancer cells. Angewandte Chemie, International Edition. 2018;**57**:15832-15835. DOI: 10.1002/anie.201811338

[91] Asano A, Yamada T, Taniguchi T, Sasaki M, Yoza K, Doi M. Ascidiacyclamides containing oxazoline and thiazole motifs assume square conformations and show high cytotoxicity. Journal of Peptide Science. 2018;**24**:e3120. DOI: 10.1002/psc.3120

[92] Chen Q-Y, Liu Y, Cai W, Luesch H. Improved total synthesis and biological evaluation of potent apratoxin S4 based anticancer agents with differential stability and further enhanced activity. Journal of Medicinal Chemistry. 2014;**57**:3011-3029. DOI: 10.1021/jm4019965

[93] Cai W, Chen Q-Y, Dang LH, Luesch H. Apratoxin S10, a dual inhibitor of angiogenesis and cancer cell growth to treat highly vascularized tumors. ACS Medicinal Chemistry Letters. 2017;**8**:1007-1012. DOI: 10.1021/ acsmedchemlett.7b00192

[94] Cai W, Ratnayake R, Gerber MH, Q-y C, Yu Y, Derendorf H, et al. Development of apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent and its preliminary evaluation in an orthotopic patient-derived

**77**

*Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds*

*DOI: http://dx.doi.org/10.5772/intechopen.82741*

xenograft (PDX) model. Investigational New Drugs. 2018;**10**. DOI: 10.1007/

[95] Onda Y, Masuda Y, Yoshida M, Doi T. Conformation-based design and synthesis of apratoxin a mimetics modified at the α,β-unsaturated thiazoline moiety. Journal of Medicinal Chemistry. **2017**(60):6751-6765. DOI: 10.1021/acs.jmedchem.7b00833

s10637-018-0647-0

*Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds DOI: http://dx.doi.org/10.5772/intechopen.82741*

xenograft (PDX) model. Investigational New Drugs. 2018;**10**. DOI: 10.1007/ s10637-018-0647-0

*Heterocycles - Synthesis and Biological Activities*

[82] Tumey N, Leverett CA, Vetelino B, Li F, Rago B, Han X, et al. Optimization of tubulysin antibody-drug conjugates: A case study in addressing ADC metabolism. ACS Medicinal Chemistry Letters. 2016;**7**:977-982. DOI: 10.1021/

activity of largazole, a depsipeptide inhibitor of the histone deacetylases. Journal of the American Chemical Society. 2011;**133**:12474-12477. DOI:

[89] Kim B, Ratnayake R, Lee H, Shi G, Zeller SL, Li C, et al. Synthesis and biological evaluation of largazole zincbinding group analogs. Bioorganic & Medicinal Chemistry. 2017;**25**:3077-3086.

DOI: 10.1016/j.bmc.2017.03.071

10.1002/anie.201811338

Sasaki M, Yoza K, Doi M. Ascidiacyclamides containing oxazoline and thiazole motifs assume square conformations and show high cytotoxicity. Journal of Peptide Science. 2018;**24**:e3120. DOI: 10.1002/psc.3120

10.1021/jm4019965

[90] Sun S, Oliveira B, Jiménez-Osés G, Bernardes GJL. Radical-mediated thiol-ene strategy for photoactivation of thiol-containing drugs in cancer cells. Angewandte Chemie, International Edition. 2018;**57**:15832-15835. DOI:

[91] Asano A, Yamada T, Taniguchi T,

[92] Chen Q-Y, Liu Y, Cai W, Luesch H. Improved total synthesis and biological evaluation of potent apratoxin S4 based anticancer agents with differential stability and further enhanced activity. Journal of Medicinal Chemistry. 2014;**57**:3011-3029. DOI:

[93] Cai W, Chen Q-Y, Dang LH, Luesch H. Apratoxin S10, a dual inhibitor of angiogenesis and cancer cell growth to treat highly vascularized tumors. ACS Medicinal Chemistry Letters. 2017;**8**:1007-1012. DOI: 10.1021/ acsmedchemlett.7b00192

[94] Cai W, Ratnayake R, Gerber MH, Q-y C, Yu Y, Derendorf H, et al. Development of apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent and its preliminary evaluation in an orthotopic patient-derived

10.1021/ja205972n

[83] Reddy JA, Dorton R, Bloomfield A, Nelson M, Dircksen C, Vetzel M, et al. Pre-clinical evaluation of EC1456, a folate-tubulysin anti-cancer therapeutic. Scientific Reports. 2018;**8**:8943-8943. DOI: 10.1038/s41598-018-27320-5

[84] Ying Y, Taori K, Kim H, Hong J, Luesch H. Total synthesis and molecular target of largazole, a histone deacetylase inhibitor. Journal of the American Chemical Society. 2008;**130**:8455-8459.

[85] Poli G, Di Fabio R, Ferrante L, Summa V, Botta M. Largazole analogues

as histone deacetylase inhibitors and anticancer agents: An overview of structure-activity relationships. ChemMedChem. 2017;**12**:1917-1926. DOI: 10.1002/cmdc.201700563

[86] Clausen DJ, Smith WB, Haines BE, Wiest O, Bradner JE, Williams RM. Modular synthesis and biological activity of pyridyl-based analogs of the potent class I histone deacetylase inhibitor Largazole. Bioorganic & Medicinal Chemistry. 2015;**23**:5061-5074. DOI: 10.1016/j.bmc.2015.03.063

[87] Almaliti J, Al-Hamashi AA, Negmeldin AT, Hanigan CL, Perera L, Pflum MKH, et al. Largazole analogues embodying radical changes in the depsipeptide ring: Development of a more selective and highly potent analogue. Journal of Medicinal

Chemistry. 2016;**59**:10642-10660. DOI:

[88] Cole KE, Dowling DP, Boone MA,

Structural basis of the antiproliferative

10.1021/acs.jmedchem.6b01271

Phillips AJ, Christianson DW.

acsmedchemlett.6b00195

DOI: 10.1021/ja8013727

**76**

[95] Onda Y, Masuda Y, Yoshida M, Doi T. Conformation-based design and synthesis of apratoxin a mimetics modified at the α,β-unsaturated thiazoline moiety. Journal of Medicinal Chemistry. **2017**(60):6751-6765. DOI: 10.1021/acs.jmedchem.7b00833

**79**

(HO•

**Chapter 6**

**Abstract**

Heterocycles

phase transfer catalyst, KO2

), superoxide anion radical O2

**1. Introduction**

*Sundaram Singh and Savita Kumari*

One-Pot-Condensation Reaction

1,3-Diketone and Aldehydes Using

*In Situ* Generated Superoxide Ion:

A Rapid Synthesis of Structurally

A novel, convenient one-pot multicomponent synthesis of tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-one derivatives has been reported in the presence of tetraethylammonium superoxide under non-aqueous condition. The superoxide induced three-component reaction of various aromatic aldehydes, 2-aminobenzimadazole/2-aminobenzothiazole and dimedone/1,3- cyclohexanedione produced tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-one derivatives at room temperature under the mild reaction conditions. The tetraethylammonium superoxide has been generated by phase transfer reaction of potassium superoxide and tetraethylammonium bromide in dry DMF at room temperature. The present study extended the applicability of tetraethylammonium bromide as a phase transfer catalyst for the efficient use of superoxide ion in multi-component synthesis of structurally diverse drug-like complex heterocycles (quinazolines).

**Keywords:** superoxide ion, multicomponent reaction, Tetraethylammonium bromide,

The importance of oxygen in sustaining life is unquestionable but the aerobic life-style is fraught with danger. However, some recent reports about oxygen toxicity have caused much concern among the whole scientific community. The oxygen toxicity is due to various reactive oxygen species (ROS) such as hydroxyl radical

(HOCl), hydrogen peroxide (H2O2), singlet oxygen and ozone are also included in this category, although they are not free radicals but can lead to free radical reaction. Out of all the reactive oxygen species, superoxide anion radical is probably the most important ROS, which has come to the forefront of current chemical and

• <sup>−</sup>, and perhydroxyl radical. Hypochlorous acid

Diverse Drug-Like Complex

of Heterocyclic Amine,

#### **Chapter 6**

## One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using *In Situ* Generated Superoxide Ion: A Rapid Synthesis of Structurally Diverse Drug-Like Complex Heterocycles

*Sundaram Singh and Savita Kumari*

#### **Abstract**

A novel, convenient one-pot multicomponent synthesis of tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-one derivatives has been reported in the presence of tetraethylammonium superoxide under non-aqueous condition. The superoxide induced three-component reaction of various aromatic aldehydes, 2-aminobenzimadazole/2-aminobenzothiazole and dimedone/1,3- cyclohexanedione produced tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-one derivatives at room temperature under the mild reaction conditions. The tetraethylammonium superoxide has been generated by phase transfer reaction of potassium superoxide and tetraethylammonium bromide in dry DMF at room temperature. The present study extended the applicability of tetraethylammonium bromide as a phase transfer catalyst for the efficient use of superoxide ion in multi-component synthesis of structurally diverse drug-like complex heterocycles (quinazolines).

**Keywords:** superoxide ion, multicomponent reaction, Tetraethylammonium bromide, phase transfer catalyst, KO2

#### **1. Introduction**

The importance of oxygen in sustaining life is unquestionable but the aerobic life-style is fraught with danger. However, some recent reports about oxygen toxicity have caused much concern among the whole scientific community. The oxygen toxicity is due to various reactive oxygen species (ROS) such as hydroxyl radical (HO• ), superoxide anion radical O2 • <sup>−</sup>, and perhydroxyl radical. Hypochlorous acid (HOCl), hydrogen peroxide (H2O2), singlet oxygen and ozone are also included in this category, although they are not free radicals but can lead to free radical reaction. Out of all the reactive oxygen species, superoxide anion radical is probably the most important ROS, which has come to the forefront of current chemical and

biochemical research for the two reasons [1–4]. First superoxide ion as a biochemical species which causes many diseases such as cancer, ageing, inflammation, heart attack and lung injury, etc. More recently, it has been implicated to play a key role in both aging and cancer. Second superoxide ion as a novel reagent. Further from its elementary reactivity pattern, this anion radical has been recognized as a multipotent reagent, which acts as a base, nucleophile, oxidant and reductant. In view of these two points, superoxide research has become an area of interdisciplinary investigation [5–13].

Multi-component reactions (MCRs), in which multiple reactions are combined into one synthetic operation, have been used extensively to form carbon-carbon bonds in synthetic chemistry. Such reactions offer greater possibilities for molecular diversity per step with minimum reaction time, labor, cost, and waste production. The rapid assembly of molecular diversity utilizing MCRs has gained a great deal of attention, most notably for the construction of 'drug-like' libraries [14–20].

Quinazolines are very interesting heterocycles [21–25] as they serve as building blocks in numerous natural and synthetic products [26]. They exhibit a wide spectrum of biological and pharmacological activities such as propyl hydroxylase inhibitor [27], antidiabetics [28], anti-inflammatory [29], antiviral [30], antimicrobial [31], antineoplastic [32] and potent immunosuppressive agents [33]. Moreover, benzimidazolo quinazolines have also been an important class of heterocyclic compounds in drug research, as they are formed from both biodynamic heterosystems, benzimidazole and quinazoline, which have shown significant anticancer activities. Many useful methods, have been reported for synthesis of tetrahydrobenzoimidazo [2,1-b] quinazolin-1(2H)-ones ring system skeletons, such as the condensation of aminoazoles with benzylidene compounds, or three-component condensation of 2-aminobenzothiazole or 2-aminobenzimidazole and an aldehyde with cyclic 1,3-diketone. These reported methodologies produce good results in many cases [34, 35]. However, some of them suffer with certain limitations such as expensive catalysts, low yields of products, long reaction times, tedious procedures for preparations of catalysts, and tedious workup conditions [36–40]. Thus, there is enough room for further investigation in this direction. With a view to investigate the behavior of the superoxide ion in multicomponent organic synthesis, which is of importance in itself and further to assess its synthetic scope, the reaction of this novel reagent was studied.

#### **2. Results and discussion**

In continuation of our ongoing program on superoxide research and the synthesis of biologically active compounds, it is our current endeavor to extent the applicability of Et4NO2 for the synthesis of tetraheterocyclicBenzimidazolo/ benzothiazolo quinazolin-1-one ring systems **4** by a one-pot three-component condensation reaction of various aromatic aldehydes **2** and 1,3-diketones **3** with 2-aminobenzimidazole/2-aminobenzothiazole **1** using tetraethylammonium superoxide under non aqueous conditions (**Figure 1**).

In order to achieve the optimum yield of the product, the effect of various parameters such as effect of solvents (DMF, DMSO, and CH3CN) and molar proportion of the reactants were investigated in detail using benzaldehyde **2**, dimedone **3** with 2-aminobenzimidazole **1** as a model reaction.

To investigate the effect of solvents, the model reaction was carried out in different aprotic solvents. The results obtained clearly indicate that DMF was the best solvent among all investigated solvents in terms of product yield and the reaction time (**Table 1**).

**81**

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using…*

*One-pot synthesis of compounds 4 by the three-component condensation reaction of various aldehydes and 1,3-diketones with 2-aminobenzimidazole/2-aminobenzothiazole under superoxide ion at room temperature.*

**Entry Solvents Time %Yield** Dichloromethane 12 h Trace Acetonitrile 8 h 70 Tetrahydrofuran 14 h 42 Dimethylsulfoxide 20 h Trace Dimethylformamide 6 h 88

**Entry Reactants molar ratio Product yield\* (%)**

**Benzaldehydes:dimidone:2-aminobezimidazole:KO2:Et4NBr** 1.0 1.0 1.0 1.0 1.0 40 1.0 1.0 1.0 1.0 0.5 38 1.0 1.0 1.0 1.0 0.25 28 1.0 1.0 1.0 2.5 1.25 69 **1.0 1.0 1.0 4.0 2.00 88** 1.0 1.0 1.0 6.0 3.00 90

In order to establish the reactants molar ratio on the yield of product the model

A perusal of the table clearly indicates the profound effect of the concentration of KO2 and Et4NBr on the yield of the product **4a**. As regards the ratio of KO2 and Et4NBr, it is evident from the entries 1, 2 and 3 that with the diminution of the concentration of Et4NBr, the yield of product **4a** decreases. But as may be seen only a little difference in the yield of the product in the case of entries 1 and 2, the ratio of KO2 and Et4NBr was further kept to be 2:1. Therefore, in subsequent studies, the concentration of KO2 has been increased manifold but the ratio of KO2 and Et4NBr was all along maintained to be 2:1. Furthermore, in case of entries 5 and 6, there is just a 2% increase in the yield of the product and for that 2% increase, the concentration of KO2 and Et4NBr have been increased

reaction was carried out in different concentration of reactants (**Table 2**).

*DOI: http://dx.doi.org/10.5772/intechopen.81146*

**Figure 1.**

**Table 1.**

**Table 2.**

*Effect of solvents on the yield of the product 4a.*

*\*Isolated yield based on aldehyde.*

*Optimized condition has been shown by bold letter (entry 5).*

*Effect of reactants molar ratio on the yield of product 4a.*

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using… DOI: http://dx.doi.org/10.5772/intechopen.81146*

#### **Figure 1.**

*Heterocycles - Synthesis and Biological Activities*

investigation [5–13].

**2. Results and discussion**

oxide under non aqueous conditions (**Figure 1**).

2-aminobenzimidazole **1** as a model reaction.

biochemical research for the two reasons [1–4]. First superoxide ion as a biochemical species which causes many diseases such as cancer, ageing, inflammation, heart attack and lung injury, etc. More recently, it has been implicated to play a key role in both aging and cancer. Second superoxide ion as a novel reagent. Further from its elementary reactivity pattern, this anion radical has been recognized as a multipotent reagent, which acts as a base, nucleophile, oxidant and reductant. In view of these two points, superoxide research has become an area of interdisciplinary

Multi-component reactions (MCRs), in which multiple reactions are combined into one synthetic operation, have been used extensively to form carbon-carbon bonds in synthetic chemistry. Such reactions offer greater possibilities for molecular diversity per step with minimum reaction time, labor, cost, and waste production. The rapid assembly of molecular diversity utilizing MCRs has gained a great deal of

Quinazolines are very interesting heterocycles [21–25] as they serve as building blocks in numerous natural and synthetic products [26]. They exhibit a wide spectrum of biological and pharmacological activities such as propyl hydroxylase inhibitor [27], antidiabetics [28], anti-inflammatory [29], antiviral [30], antimicrobial [31], antineoplastic [32] and potent immunosuppressive agents [33]. Moreover, benzimidazolo quinazolines have also been an important class of heterocyclic compounds in drug research, as they are formed from both biodynamic heterosystems, benzimidazole and quinazoline, which have shown significant anticancer activities. Many useful methods, have been reported for synthesis of tetrahydrobenzoimidazo [2,1-b] quinazolin-1(2H)-ones ring system skeletons, such as the condensation of aminoazoles with benzylidene compounds, or three-component condensation of 2-aminobenzothiazole or 2-aminobenzimidazole and an aldehyde with cyclic 1,3-diketone. These reported methodologies produce good results in many cases [34, 35]. However, some of them suffer with certain limitations such as expensive catalysts, low yields of products, long reaction times, tedious procedures for preparations of catalysts, and tedious workup conditions [36–40]. Thus, there is enough room for further investigation in this direction. With a view to investigate the behavior of the superoxide ion in multicomponent organic synthesis, which is of importance in itself and further to

attention, most notably for the construction of 'drug-like' libraries [14–20].

assess its synthetic scope, the reaction of this novel reagent was studied.

In continuation of our ongoing program on superoxide research and the synthesis of biologically active compounds, it is our current endeavor to extent the applicability of Et4NO2 for the synthesis of tetraheterocyclicBenzimidazolo/ benzothiazolo quinazolin-1-one ring systems **4** by a one-pot three-component condensation reaction of various aromatic aldehydes **2** and 1,3-diketones **3** with 2-aminobenzimidazole/2-aminobenzothiazole **1** using tetraethylammonium super-

In order to achieve the optimum yield of the product, the effect of various parameters such as effect of solvents (DMF, DMSO, and CH3CN) and molar proportion of the reactants were investigated in detail using benzaldehyde **2**, dimedone **3** with

To investigate the effect of solvents, the model reaction was carried out in different aprotic solvents. The results obtained clearly indicate that DMF was the best solvent among all investigated solvents in terms of product yield and the reaction

**80**

time (**Table 1**).

*One-pot synthesis of compounds 4 by the three-component condensation reaction of various aldehydes and 1,3-diketones with 2-aminobenzimidazole/2-aminobenzothiazole under superoxide ion at room temperature.*


#### **Table 1.**

*Effect of solvents on the yield of the product 4a.*


*Optimized condition has been shown by bold letter (entry 5).*

#### **Table 2.**

*Effect of reactants molar ratio on the yield of product 4a.*

In order to establish the reactants molar ratio on the yield of product the model reaction was carried out in different concentration of reactants (**Table 2**).

A perusal of the table clearly indicates the profound effect of the concentration of KO2 and Et4NBr on the yield of the product **4a**. As regards the ratio of KO2 and Et4NBr, it is evident from the entries 1, 2 and 3 that with the diminution of the concentration of Et4NBr, the yield of product **4a** decreases. But as may be seen only a little difference in the yield of the product in the case of entries 1 and 2, the ratio of KO2 and Et4NBr was further kept to be 2:1. Therefore, in subsequent studies, the concentration of KO2 has been increased manifold but the ratio of KO2 and Et4NBr was all along maintained to be 2:1. Furthermore, in case of entries 5 and 6, there is just a 2% increase in the yield of the product and for that 2% increase, the concentration of KO2 and Et4NBr have been increased

substantially (6 fold and 3 fold respectively). As a result, considering the high cost of KO2 and Et4NBr, the entry 5, with the reactants ratio **1:1:1:4:2**, has been selected as the optimum ratio.

The scope and limitations of this reaction were fully illustrated with various *ortho-, meta- and para-substituted* benzaldehydes in the presence of 2-aminobenzimidazole and 2-aminobenzothiazole.

As indicated in **Table 3**, the reaction proceeded efficiently with both electron-withdrawing and electron releasing *ortho-, meta- and para-*substituted benzaldehydes.

The products were identified by their physical and spectral data, which were in full agreement with the reported values.

**83**

**Figure 2.**

*derivatives (4a-o).*

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using…*

The proposed mechanism for the formation of tetraheterocyclicbenzimidazolo/ benzothiazolo quinazolin-1-ones ring system is given in **Figure 2**. The reaction was initiated by the abstraction of proton from 1,3-diketones **3** by tetraethylammonium superoxide which was *in situ* generated by the phase transfer reaction of potassium superoxide with tetraethylammonium bromide. Now, Knoevenagel condensation takes place between benzaldehyde **2** and subsequently, by dehydration, olefin 3-benzylidene-2,4-hexanedione **5** is produced. Then 2-aminobenzimidazole/2-aminobenzothiazole**1** is reacted with compound **5** through a Michael addition to produce a product of type **6** and after cyclisation to afford tetraheterocyclicbenzimidazolo/

Potassium superoxide (1.42 g, 0.02 mol) and tetraethylammonium bromide (2.10 g, 0.01 mol) were weighed under nitrogen atmosphere using an atmosbag and were transferred into a three-necked R. B. flask, dry DMF (20 mL) was added to it and the mixture was agitated magnetically for 15 min to facilitate the formation of tetraethylammoniumsuperoxide. To the stirred reaction mixture, dimedone (0.70 g, 0.005 mol) **3** were added. After 10 min, benzaldehyde (0.53 g, 0.005 mol) **2** and 2-aminobenzimidazole (0.665 g, 0.005 mmol) **1** were introduced, and the stirring was continued 6 h. After the reaction was over as indicated by TLC, mixture was treated with cold brine solution (2 mL) followed by saturated sodium hydrogen carbonate solution (2 mL) to decompose the unreacted KO2. The mixture was then extracted with dichloromethane (3 × 15 mL) and the combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated to give

the products **4a**, which were purified by column chromatography.

*Plausible mechanism for the formation of tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-one* 

**2.1 Mechanism for the synthesis of tetraheterocyclicbenzimidazolo/**

*DOI: http://dx.doi.org/10.5772/intechopen.81146*

**benzothiazolo quinazolin-1-ones**

benzothiazolo quinazolin-1-one ring systems **4**.

**Table 3.** *Synthesis of tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-ones.*

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using… DOI: http://dx.doi.org/10.5772/intechopen.81146*

#### **2.1 Mechanism for the synthesis of tetraheterocyclicbenzimidazolo/ benzothiazolo quinazolin-1-ones**

The proposed mechanism for the formation of tetraheterocyclicbenzimidazolo/ benzothiazolo quinazolin-1-ones ring system is given in **Figure 2**. The reaction was initiated by the abstraction of proton from 1,3-diketones **3** by tetraethylammonium superoxide which was *in situ* generated by the phase transfer reaction of potassium superoxide with tetraethylammonium bromide. Now, Knoevenagel condensation takes place between benzaldehyde **2** and subsequently, by dehydration, olefin 3-benzylidene-2,4-hexanedione **5** is produced. Then 2-aminobenzimidazole/2-aminobenzothiazole**1** is reacted with compound **5** through a Michael addition to produce a product of type **6** and after cyclisation to afford tetraheterocyclicbenzimidazolo/ benzothiazolo quinazolin-1-one ring systems **4**.

Potassium superoxide (1.42 g, 0.02 mol) and tetraethylammonium bromide (2.10 g, 0.01 mol) were weighed under nitrogen atmosphere using an atmosbag and were transferred into a three-necked R. B. flask, dry DMF (20 mL) was added to it and the mixture was agitated magnetically for 15 min to facilitate the formation of tetraethylammoniumsuperoxide. To the stirred reaction mixture, dimedone (0.70 g, 0.005 mol) **3** were added. After 10 min, benzaldehyde (0.53 g, 0.005 mol) **2** and 2-aminobenzimidazole (0.665 g, 0.005 mmol) **1** were introduced, and the stirring was continued 6 h. After the reaction was over as indicated by TLC, mixture was treated with cold brine solution (2 mL) followed by saturated sodium hydrogen carbonate solution (2 mL) to decompose the unreacted KO2. The mixture was then extracted with dichloromethane (3 × 15 mL) and the combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated to give the products **4a**, which were purified by column chromatography.

#### **Figure 2.**

*Plausible mechanism for the formation of tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-one derivatives (4a-o).*

*Heterocycles - Synthesis and Biological Activities*

selected as the optimum ratio.

benzaldehydes.

imidazole and 2-aminobenzothiazole.

full agreement with the reported values.

substantially (6 fold and 3 fold respectively). As a result, considering the high cost of KO2 and Et4NBr, the entry 5, with the reactants ratio **1:1:1:4:2**, has been

The scope and limitations of this reaction were fully illustrated with various *ortho-, meta- and para-substituted* benzaldehydes in the presence of 2-aminobenz-

The products were identified by their physical and spectral data, which were in

As indicated in **Table 3**, the reaction proceeded efficiently with both electron-withdrawing and electron releasing *ortho-, meta- and para-*substituted

**82**

**Table 3.**

*Synthesis of tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-ones.*

All the products were characterized by IR and 1 H NMR (because of low solubility of compounds **4a-o**, 13C NMR was not obtained).

**3,3–Dimethyl–12–phenyl–3,4,6,12–tetrahydrobenzo[4,5]imidazo[2,1-b] quinazolin–1(2H)–one (4a):** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup> ) 3445, 2885, 1640, 1618, 1610, 1565 cm<sup>−</sup><sup>1</sup> ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.16 (br. s, 1H, NH), 7.39–7.30 (m, 6H), 7.23 (d, *J* = 8.0 Hz, 1H), 7.07–7.04 (m, 1H), 6.98–6.95 (m, 1H), 6.44 (s, 1H), 2.26 (d, *J* = 16.0 Hz, 2H), 2.06 (d, *J* = 16.0 Hz, 2H), 1.06 (s, 3H), 0.92 (s, 3H). Anal. Calcd for C22H21N3O: C, 76.94; H, 6.16; N, 12.24; O, 4.66. Found: C, 76.90; H, 6.20; N, 12.26; O, 4.64.

**12–(4–Methoxyphenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4b):** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup> ) 3391, 2850, 1670, 1644, 1610, 1590 cm<sup>−</sup><sup>1</sup> ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.06 (br. s, 1H, NH), 7.36 (d, *J* = 8.0 Hz, 1H), 7.26–7.24 (m, 3H), 7.04 (t, *J* = 7.5 Hz, 1H), 6.95 (t, *J* = 7.5 Hz, 1H), 6.78 (d, *J* = 8.5 Hz, 2H), 6.36 (s, 1H), 3.65 (s, 3H), 2.64–2.52 (m, 2H), 2.25 (d, *J* = 16.0 Hz, 1H), 2.05 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 3H), 0.94 (s, 3H). Anal Calcd for C23H23N3O2: C, 73.97; H, 6.21; N, 11.25; O, 8.57. Found: C, 73.92; H, 6.26; N, 11.23; O, 8.59.

**12–(4–Chlorophenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4c):** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup> ) 3440, 2934, 1655, 1650, 1613, 1580 cm<sup>−</sup><sup>1</sup> ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.10 (br. s, 1H, NH), 7.36 (d, *J* = 7.5 Hz, 1H), 7.33 (d, *J* = 6.5 Hz, 2H), 7.24 (s, 2H), 7.15 (s, 1H), 7.04 (s, 1H), 6.95 (s, 1H), 6.41 (s, 1H), 2.63 (d, *J* = 16.0 Hz, 2H), 2.26 (d, *J* = 16.0 Hz, 2H), 1.06 (s, 3H), 0.93 (s, 3H). Anal. Calcd for C22H20ClN3O: C, 69.93; H, 5.34; Cl, 9.38; N, 11.12; O, 4.23. Found: C, 69.90; H, 5.37; Cl, 9.34; N, 11.15; O, 4.24.

**12–(4–Bromophenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4d):** M.p. >300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup> ) 3441, 2956, 1645, 1614, 1590, 1566 cm<sup>−</sup><sup>1</sup> ; 1 H-NMR (500 MHz, DMSO-*d6*): *δ* = 10.01 (br. s, 1H, NH), 6.99–7.89 (m, Ar–H), 6.43 (s, 1H), 2.59–2.67 (m, 2H), 2.20 (d, *J* = 16.00 Hz, 1H), 2.00 (d, *J* = 16.01 Hz, 1H) 1.05 (s, 3H), 0*.*94 (s, 3H). Anal. Calcd for C22H20BrN3O: C, 62.57; H, 4.77; Br, 18.92; N, 9.95; O, 3.79. Found: C, 62.67; H, 4.86; Br, 18.80; N, 9.83; O, 3.90.

**12–(4–Hydroxyphenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4e):** M.p. *>* 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup> ) 3449, 2891, 1642, 1613, 1587, 1566 cm<sup>−</sup><sup>1</sup> ; 1 H-NMR (500 MHz, DMSO-*d6*) *δ* = 11.02 (br. s, 1H, NH), 9.33 (s, 1H, OH), 6.61–7.36 (m, 8H, Ar–H), 6.18 (s, 1H), 2.51–2.74 (m, 2H), 2.25 (d, *J* = 9.24 Hz, 1H), 2.05(d, *J* = 8.94 Hz, 1H), 1.07 (s, 3H), 0*.*96 (s, 3H), Anal. Calcd for C22H21N3O2: C, 73.52; H, 5.89; N, 11.69; O, 8.90. Found: C, 73.63; H, 5.97; N, 11.80; O, 8.71.

**12–(3–Chlorophenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4f)** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup> ) 3400, 2891, 1660, 1652, 1613, 1575 cm<sup>−</sup><sup>1</sup> ; 1 H NMR (500 MHz, DMSO−*d6*): *δ* = 11.18 (br. s, 1H, NH), 7.46 (s, 1H), 7.39 (d, *J* = 8.0 Hz, 1H), 7.30–7.21 (m, 5H), 7.06 (s, 1H), 6.98 (s, 1H), 6.46 (s, 1H), 2.58 (d, *J* = 16.0 Hz, 1H), 2.26 (d, *J* = 16.0 Hz, 1H), 2.08 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 3H), 0.93 (s, 3H). Anal. Calcd for C22H20ClN3O: C, 69.93; H, 5.34; Cl, 9.38; N, 11.12; O, 4.23. Found: C, 69.90; H, 5.37; Cl, 9.35; N, 11.14; O, 4.24.

**3,3–Dimethyl–12–(2–nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4 g):** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup> ) 3398, 2972, 1664, 1645, 1618, 1594 cm<sup>−</sup><sup>1</sup> ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.18 (br. s, 1H, NH), 7.46 (s, 1H), 7.31–7.19 (m, 5H), 7.06 (t, *J* = 7.5 Hz, 1H), 6.98 (t, *J* = 7.5 Hz, 1H), 6.46 (s, 1H), 2.62 (d, *J* = 16.0 Hz, 1H), 2.55 (s, 1H), 2.26 (d, *J* = 16.0 Hz, 1H), 2.08 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 2H), 0.93 (s, 2H). Anal. Calcd

**85**

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using…*

for C22H20N4O3: C, 68.03; H, 5.19; N, 14.42; O, 12.36. Found: C, 68.07; H, 5.15; N,

; 1

> ; 1

(d, *J* = 16.0 Hz, 1H), 2.06 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 3H), 0.91 (s, 3H). Anal. Calcd for C22H20N4O3: C, 68.03; H, 5.19; N, 14.42; O, 12.36. Found: C, 68.04; H,

**12–(4–Methoxyphenyl)–3,4,6,12–tetrahydrobenzo[4,5]imidazo[2,1-b]**

**12–(3–Nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5]imidazo[2,1-b]quin-**

**3,3–Dimethyl–12–phenyl–2,3,4,12–tetrahydro–1H–benzo[4,5]thiazolo[2,3–b]**

Hz, 1H), 7.43 (dd, *J* = 17.5, 7.7 Hz, 3H), 7.28 (dd, *J* = 16.0, 3H), 7.20 (dd, *J* = 16.0, 8.0 Hz, 2H), 6.51 (s, 1H), 2.47–2.36 (m, 2H), 2.24 (d, *J* = 16.0 Hz, 1H), 2.05

(d, *J* = 16.0 Hz, 1H), 1.02 (s, 3H), 0.86 (s, 3H). Anal. Calcd for C22H20N2OS: C, 73.30; H, 5.59; N, 7.77; O, 4.44; S, 8.89. Found: C, 73.33; H, 5.56; N, 7.79; O, 4.41; S, 8.88. 3,3–Dimethyl–12–(4-methylphenyl)–2,3,4,12–tetrahydro–1H–benzo[4,5]

(d, *J* = 8 Hz, 2H), 7.28–7.22 (m, 1H), 7.18–7.15 (m, 2H), 7.06 (d, *J* = 8 Hz, 2H), 6.47 (s, 1H), 2.49 (s, 2H), 2.28–2.17 (m, 5H), 1.09 (s, 3H), 0.97 (s, 3H). Anal. Calcd for C23H22N2OS: C, 73.77; H, 5.92; N, 7.48; O, 4.27; S, 8.56. Found: C, 73.68; H, 5.71; N,

**3,3–Dimethyl–12–(4-bromophenyl)–2,3,4,12–tetrahydro–1H–benzo[4,5]**

DMSO–*d6*): *δ* = 7.47 (d, *J* = 8 Hz, 1H), 7.37–7.28 (m, 5H), 7.19 (d, *J* = 8 Hz, 1H), 7.06

(br. s, 1H, NH), 8.12 (d, *J* = 8.5 Hz, 2H), 7.61 (d, *J* = 9.0 Hz, 2H), 7.40 (d, *J* = 7.5 Hz, 1H), 7.23 (d, *J* = 8.0 Hz, 1H), 7.07 (t, *J* = 7.5 Hz, 1H), 6.96 (t, *J* = 7.5 Hz, 1H), 6.60

)

)

) 3398, 2976,

) 3412, 2872, 2855, 1670,

) 3428, 2965, 1680,

H NMR (500 MHz,

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.26

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.27

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.07 (br. s, 1H,

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.28 (br. s, 1H, NH),

H NMR (500 MHz, DMSO–*d6*): *δ* = 7.79 (d, *J* = 10.0

H NMR (500 MHz, DMSO–*d6*): *δ* = 7.49–7.47 (m, 1H), 7.34

**3,3–Dimethyl–12–(3–nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4 h):** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup>

(br. s, 1H, NH), 8.27 (s, 1H), 8.04 (d, *J* = 8.0 Hz, 1H), 7.73 (d, *J* = 7.5 Hz, 1H), 7.56 (t, *J* = 8.0 Hz, 1H), 7.40 (d, *J* = 8.0 Hz, 1H), 7.29 (d, *J* = 8.0 Hz, 1H), 7.07 (t, *J* = 7.5 Hz, 1H), 6.97 (t, *J* = 7.5 Hz, 1H), 6.65 (s, 1H), 2.27 (d, *J* = 16.0 Hz, 2H), 2.07 (d, *J* = 16.0 Hz, 2H), 1.06 (s, 3H), 0.91 (s, 3H). Anal. Calcd for C22H20N4O3: C, 68.03;

H, 5.19; N, 14.42; O, 12.36. Found: C, 68.08; H, 5.14; N, 14.44; O, 12.34. **3,3–Dimethyl–12–(4–nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4i):** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup>

(s, 1H), 2.65 (d, *J* = 16.0 Hz, 1H), 2.54 (d, *J* = 16.0 Hz, 1H), 2.27

**quinazolin–1(2H)–one (4j):** M.p. = 238–240°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup>

NH), 7.36 (d, *J* = 8.0 Hz, 1H), 7.26–7.22 (m, 3H), 7.06–7.01 (m, 1H), 6.95 (t, *J* = 7.2 Hz, 1H), 6.78 (d, *J* = 8.0 Hz, 2H), 6.37 (s, 1H), 3.65 (s, 3H), 2.68 (d, *J* = 5.0 Hz, 2H), 2.29 (dd, *J* = 10.5, 5.0 Hz, 1H), 2.22 (dd, *J* = 16.0, 5.0 Hz, 1H), 2.02–1.93 (m, 1H), 1.88–1.80 (m, 1H). Anal. Calcd for C21H19N3O2: C, 73.03; H, 5.54;

8.26 (s, 1H), 8.03 (d, *J* = 8.5 Hz, 1H), 7.70 (d, *J* = 7.5 Hz, 1H), 7.54 (t, *J* = 8.0 Hz, 1H), 7.40 (d, *J* = 8.0 Hz, 1H), 7.26 (d, *J* = 7.5 Hz, 1H), 7.06 (t, *J* = 7.4 Hz, 1H), 6.96 (t, *J* = 7.5 Hz, 1H), 6.66 (s, 1H), 2.40–2.18 (m, 2H), 1.93 (dd, *J* = 16.0, 2H);. Anal. Calcd for C20H16N4O3: C, 66.66; H, 4.48; N, 15.55; O, 13.32. Found: C,

; 1

N, 12.17; O, 9.26. Found: C, 73.01; H, 5.56; N, 12.14; O, 9.29.

**azolin–1(2H)–one(4 k):** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup>

**quinazolin–1–one (4 l):** M.p. = 208–210°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup>

**thiazolo[2,3–b]quinazolin–1–one (4n):** M.p. 182–184°C. <sup>1</sup>

; 1

; 1

66.64; H, 4.50; N, 15.53; O, 13.34.

thiazolo[2,3–b]quinazolin–1–one(4 m):

1655, 1589, 1516, 1370 cm<sup>−</sup><sup>1</sup>

M.p. = 203–205°C. 1

7.60; O, 4.35; S, 8.70.

*DOI: http://dx.doi.org/10.5772/intechopen.81146*

3394, 2970, 1660, 1648, 1615, 1598 cm<sup>−</sup><sup>1</sup>

3396, 2980, 1662, 1641, 1612, 1594 cm<sup>−</sup><sup>1</sup>

5.18; N, 14.40; O, 12.38.

1640, 1617, 1601 cm<sup>−</sup><sup>1</sup>

1666, 1642, 1616, 1575 cm<sup>−</sup><sup>1</sup>

14.46; O, 12.32.

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using… DOI: http://dx.doi.org/10.5772/intechopen.81146*

for C22H20N4O3: C, 68.03; H, 5.19; N, 14.42; O, 12.36. Found: C, 68.07; H, 5.15; N, 14.46; O, 12.32.

**3,3–Dimethyl–12–(3–nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4 h):** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup> ) 3394, 2970, 1660, 1648, 1615, 1598 cm<sup>−</sup><sup>1</sup> ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.26 (br. s, 1H, NH), 8.27 (s, 1H), 8.04 (d, *J* = 8.0 Hz, 1H), 7.73 (d, *J* = 7.5 Hz, 1H), 7.56 (t, *J* = 8.0 Hz, 1H), 7.40 (d, *J* = 8.0 Hz, 1H), 7.29 (d, *J* = 8.0 Hz, 1H), 7.07 (t, *J* = 7.5 Hz, 1H), 6.97 (t, *J* = 7.5 Hz, 1H), 6.65 (s, 1H), 2.27 (d, *J* = 16.0 Hz, 2H), 2.07 (d, *J* = 16.0 Hz, 2H), 1.06 (s, 3H), 0.91 (s, 3H). Anal. Calcd for C22H20N4O3: C, 68.03; H, 5.19; N, 14.42; O, 12.36. Found: C, 68.08; H, 5.14; N, 14.44; O, 12.34.

**3,3–Dimethyl–12–(4–nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4i):** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup> ) 3396, 2980, 1662, 1641, 1612, 1594 cm<sup>−</sup><sup>1</sup> ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.27 (br. s, 1H, NH), 8.12 (d, *J* = 8.5 Hz, 2H), 7.61 (d, *J* = 9.0 Hz, 2H), 7.40 (d, *J* = 7.5 Hz, 1H), 7.23 (d, *J* = 8.0 Hz, 1H), 7.07 (t, *J* = 7.5 Hz, 1H), 6.96 (t, *J* = 7.5 Hz, 1H), 6.60 (s, 1H), 2.65 (d, *J* = 16.0 Hz, 1H), 2.54 (d, *J* = 16.0 Hz, 1H), 2.27 (d, *J* = 16.0 Hz, 1H), 2.06 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 3H), 0.91 (s, 3H). Anal. Calcd for C22H20N4O3: C, 68.03; H, 5.19; N, 14.42; O, 12.36. Found: C, 68.04; H, 5.18; N, 14.40; O, 12.38.

**12–(4–Methoxyphenyl)–3,4,6,12–tetrahydrobenzo[4,5]imidazo[2,1-b] quinazolin–1(2H)–one (4j):** M.p. = 238–240°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup> ) 3398, 2976, 1666, 1642, 1616, 1575 cm<sup>−</sup><sup>1</sup> ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.07 (br. s, 1H, NH), 7.36 (d, *J* = 8.0 Hz, 1H), 7.26–7.22 (m, 3H), 7.06–7.01 (m, 1H), 6.95 (t, *J* = 7.2 Hz, 1H), 6.78 (d, *J* = 8.0 Hz, 2H), 6.37 (s, 1H), 3.65 (s, 3H), 2.68 (d, *J* = 5.0 Hz, 2H), 2.29 (dd, *J* = 10.5, 5.0 Hz, 1H), 2.22 (dd, *J* = 16.0, 5.0 Hz, 1H), 2.02–1.93 (m, 1H), 1.88–1.80 (m, 1H). Anal. Calcd for C21H19N3O2: C, 73.03; H, 5.54; N, 12.17; O, 9.26. Found: C, 73.01; H, 5.56; N, 12.14; O, 9.29.

**12–(3–Nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin–1(2H)–one(4 k):** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup> ) 3412, 2872, 2855, 1670, 1640, 1617, 1601 cm<sup>−</sup><sup>1</sup> ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.28 (br. s, 1H, NH), 8.26 (s, 1H), 8.03 (d, *J* = 8.5 Hz, 1H), 7.70 (d, *J* = 7.5 Hz, 1H), 7.54 (t, *J* = 8.0 Hz, 1H), 7.40 (d, *J* = 8.0 Hz, 1H), 7.26 (d, *J* = 7.5 Hz, 1H), 7.06 (t, *J* = 7.4 Hz, 1H), 6.96 (t, *J* = 7.5 Hz, 1H), 6.66 (s, 1H), 2.40–2.18 (m, 2H), 1.93 (dd, *J* = 16.0, 2H);. Anal. Calcd for C20H16N4O3: C, 66.66; H, 4.48; N, 15.55; O, 13.32. Found: C, 66.64; H, 4.50; N, 15.53; O, 13.34.

**3,3–Dimethyl–12–phenyl–2,3,4,12–tetrahydro–1H–benzo[4,5]thiazolo[2,3–b] quinazolin–1–one (4 l):** M.p. = 208–210°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup> ) 3428, 2965, 1680, 1655, 1589, 1516, 1370 cm<sup>−</sup><sup>1</sup> ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 7.79 (d, *J* = 10.0 Hz, 1H), 7.43 (dd, *J* = 17.5, 7.7 Hz, 3H), 7.28 (dd, *J* = 16.0, 3H), 7.20 (dd, *J* = 16.0, 8.0 Hz, 2H), 6.51 (s, 1H), 2.47–2.36 (m, 2H), 2.24 (d, *J* = 16.0 Hz, 1H), 2.05 (d, *J* = 16.0 Hz, 1H), 1.02 (s, 3H), 0.86 (s, 3H). Anal. Calcd for C22H20N2OS: C, 73.30; H, 5.59; N, 7.77; O, 4.44; S, 8.89. Found: C, 73.33; H, 5.56; N, 7.79; O, 4.41; S, 8.88.

3,3–Dimethyl–12–(4-methylphenyl)–2,3,4,12–tetrahydro–1H–benzo[4,5] thiazolo[2,3–b]quinazolin–1–one(4 m):

M.p. = 203–205°C. 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 7.49–7.47 (m, 1H), 7.34 (d, *J* = 8 Hz, 2H), 7.28–7.22 (m, 1H), 7.18–7.15 (m, 2H), 7.06 (d, *J* = 8 Hz, 2H), 6.47 (s, 1H), 2.49 (s, 2H), 2.28–2.17 (m, 5H), 1.09 (s, 3H), 0.97 (s, 3H). Anal. Calcd for C23H22N2OS: C, 73.77; H, 5.92; N, 7.48; O, 4.27; S, 8.56. Found: C, 73.68; H, 5.71; N, 7.60; O, 4.35; S, 8.70.

**3,3–Dimethyl–12–(4-bromophenyl)–2,3,4,12–tetrahydro–1H–benzo[4,5] thiazolo[2,3–b]quinazolin–1–one (4n):** M.p. 182–184°C. <sup>1</sup> H NMR (500 MHz, DMSO–*d6*): *δ* = 7.47 (d, *J* = 8 Hz, 1H), 7.37–7.28 (m, 5H), 7.19 (d, *J* = 8 Hz, 1H), 7.06

*Heterocycles - Synthesis and Biological Activities*

3391, 2850, 1670, 1644, 1610, 1590 cm<sup>−</sup><sup>1</sup>

; 1

73.92; H, 6.26; N, 11.23; O, 8.59.

3440, 2934, 1655, 1650, 1613, 1580 cm<sup>−</sup><sup>1</sup>

3441, 2956, 1645, 1614, 1590, 1566 cm<sup>−</sup><sup>1</sup>

3449, 2891, 1642, 1613, 1587, 1566 cm<sup>−</sup><sup>1</sup>

3400, 2891, 1660, 1652, 1613, 1575 cm<sup>−</sup><sup>1</sup>

3398, 2972, 1664, 1645, 1618, 1594 cm<sup>−</sup><sup>1</sup>

4.86; Br, 18.80; N, 9.83; O, 3.90.

73.63; H, 5.97; N, 11.80; O, 8.71.

1610, 1565 cm<sup>−</sup><sup>1</sup>

6.20; N, 12.26; O, 4.64.

All the products were characterized by IR and 1

ity of compounds **4a-o**, 13C NMR was not obtained).

**quinazolin–1(2H)–one (4a):** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup>

**3,3–Dimethyl–12–phenyl–3,4,6,12–tetrahydrobenzo[4,5]imidazo[2,1-b]**

(s, 1H), 2.26 (d, *J* = 16.0 Hz, 2H), 2.06 (d, *J* = 16.0 Hz, 2H), 1.06 (s, 3H), 0.92 (s, 3H). Anal. Calcd for C22H21N3O: C, 76.94; H, 6.16; N, 12.24; O, 4.66. Found: C, 76.90; H,

**12–(4–Methoxyphenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4b):** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup>

; 1

**12–(4–Chlorophenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4c):** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup>

**12–(4–Bromophenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4d):** M.p. >300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup>

; 1

**12–(4–Hydroxyphenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4e):** M.p. *>* 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup>

; 1

**12–(3–Chlorophenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4f)** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup>

**3,3–Dimethyl–12–(2–nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4 g):** M.p. > 300°C; IR (KBr, υ = cm<sup>−</sup><sup>1</sup>

(br. s, 1H, NH), 7.46 (s, 1H), 7.31–7.19 (m, 5H), 7.06 (t, *J* = 7.5 Hz, 1H), 6.98 (t, *J* = 7.5 Hz, 1H), 6.46 (s, 1H), 2.62 (d, *J* = 16.0 Hz, 1H), 2.55 (s, 1H), 2.26 (d, *J* = 16.0 Hz, 1H), 2.08 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 2H), 0.93 (s, 2H). Anal. Calcd

; 1

; 1

(br. s, 1H, NH), 7.46 (s, 1H), 7.39 (d, *J* = 8.0 Hz, 1H), 7.30–7.21 (m, 5H), 7.06 (s, 1H), 6.98 (s, 1H), 6.46 (s, 1H), 2.58 (d, *J* = 16.0 Hz, 1H), 2.26 (d, *J* = 16.0 Hz, 1H), 2.08 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 3H), 0.93 (s, 3H). Anal. Calcd for C22H20ClN3O: C, 69.93; H, 5.34; Cl, 9.38; N, 11.12; O, 4.23. Found: C, 69.90; H, 5.37; Cl, 9.35; N,

(br. s, 1H, NH), 9.33 (s, 1H, OH), 6.61–7.36 (m, 8H, Ar–H), 6.18 (s, 1H), 2.51–2.74 (m, 2H), 2.25 (d, *J* = 9.24 Hz, 1H), 2.05(d, *J* = 8.94 Hz, 1H), 1.07 (s, 3H), 0*.*96 (s, 3H), Anal. Calcd for C22H21N3O2: C, 73.52; H, 5.89; N, 11.69; O, 8.90. Found: C,

(br. s, 1H, NH), 6.99–7.89 (m, Ar–H), 6.43 (s, 1H), 2.59–2.67 (m, 2H), 2.20 (d, *J* = 16.00 Hz, 1H), 2.00 (d, *J* = 16.01 Hz, 1H) 1.05 (s, 3H), 0*.*94 (s, 3H). Anal. Calcd for C22H20BrN3O: C, 62.57; H, 4.77; Br, 18.92; N, 9.95; O, 3.79. Found: C, 62.67; H,

(s, 1H), 7.04 (s, 1H), 6.95 (s, 1H), 6.41 (s, 1H), 2.63 (d, *J* = 16.0 Hz, 2H), 2.26 (d, *J* = 16.0 Hz, 2H), 1.06 (s, 3H), 0.93 (s, 3H). Anal. Calcd for C22H20ClN3O: C, 69.93; H, 5.34; Cl, 9.38;

; 1

(br. s, 1H, NH), 7.36 (d, *J* = 7.5 Hz, 1H), 7.33 (d, *J* = 6.5 Hz, 2H), 7.24 (s, 2H), 7.15

N, 11.12; O, 4.23. Found: C, 69.90; H, 5.37; Cl, 9.34; N, 11.15; O, 4.24.

(br. s, 1H, NH), 7.36 (d, *J* = 8.0 Hz, 1H), 7.26–7.24 (m, 3H), 7.04 (t, *J* = 7.5 Hz, 1H), 6.95 (t, *J* = 7.5 Hz, 1H), 6.78 (d, *J* = 8.5 Hz, 2H), 6.36 (s, 1H), 3.65 (s, 3H), 2.64–2.52 (m, 2H), 2.25 (d, *J* = 16.0 Hz, 1H), 2.05 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 3H), 0.94 (s, 3H). Anal Calcd for C23H23N3O2: C, 73.97; H, 6.21; N, 11.25; O, 8.57. Found: C,

(m, 6H), 7.23 (d, *J* = 8.0 Hz, 1H), 7.07–7.04 (m, 1H), 6.98–6.95 (m, 1H), 6.44

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.16 (br. s, 1H, NH), 7.39–7.30

H NMR (because of low solubil-

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.06

H-NMR (500 MHz, DMSO-*d6*): *δ* = 10.01

H-NMR (500 MHz, DMSO-*d6*) *δ* = 11.02

H NMR (500 MHz, DMSO−*d6*): *δ* = 11.18

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.18

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.10

) 3445, 2885, 1640, 1618,

)

)

)

)

)

)

**84**

11.14; O, 4.24.

(d, *J* = 8 Hz, 1H), 6.45 (s, 1H), 2.47 (s, 2H), 2.29–2.20 (m, 2H), 1.07 (s, 3H), 0.91 (s, 3H), Anal. Calcd for C22H19BrN2OS: C, 60.14; H, 4.36; Br, 18.19; N, 6.38; O, 3.64; S, 7.30. Found: C, 60.35; H, 4.49; Br, 18.37; N, 6.50; O, 3.80; S, 7.45.

**3,3–Dimethyl–12–(4-methoxyphenyl)–2,3,4,12–tetrahydro–1H–benzo[4,5] thiazolo[2,3–b]quinazolin–1–one (4o**): M.p. 87–88°C. 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 7.49–7.46 (m, 2H), 7.38 (d, *J* = 8 Hz, 2H), 7.23–7.07 (m, 2H), 6.74 (d, *J* = 8 Hz, 2H), 6.44 (s, 1H), 3.62 (s, 3H), 2.48 (s, 2H), 2.31–2.17 (m, 2H), 1.06 (s, 3H), 0.93 (s, 3H). Anal. Calcd for C23H22N2O2S: C, 70.74; H, 5.68; N, 7.17; O, 8.19; S, 8.21. Found: C, 70.89; H, 5.80; N, 7.35; O, 8.39; S, 8.40.

#### **3. Conclusion**

In conclusion, the reaction of *in situ* generated O2 •<sup>−</sup> with imidazoles is able to mimic the *in vivo* biochemical reactions involved and corroborate the role of O2 •<sup>−</sup> in living cells. Since the investigation has been performed at an ambient temperature in the presence of *in situ* generated O2 •<sup>−</sup>, the results may be easily correlated with those occurring at physiological temperatures in more complex biological counterparts.

A novel synthetic route has been developed for the synthesis of tetraheterocyclic benzimidazolo/benzothiazolo quinazolin-1-one ring systems using tetraethylammonium superoxide under non aqueous condition at room temperature (mild reaction condition) within 6 h. The yield of the products was obtained up to 88% without using any tedious purification process. The applicability of tetraethylammonium bromide as an inexpensive alternative to 18-crown-6 for superoxide ion generation has been extended in present report.

#### **Acknowledgements**

The authors are thankful to IIT(BHU),Varanasi for financial support.

#### **Conflict of interest**

No conflict of interest.

#### **Author details**

Sundaram Singh\* and Savita Kumari Indian Institute of Technology (BHU), Varanasi, UP, India

\*Address all correspondence to: sundaram.apc@itbhu.ac.in

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**87**

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using…*

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[19] Hulme C, Gore V. Multi-component Reactions: Emerging Chemistry in

Current Medicinal Chemistry.

2005;**20**:557-568

2002;**9**:2085-2093

developments in the field of quinazoline chemistry. Current Organic Chemistry.

*DOI: http://dx.doi.org/10.5772/intechopen.81146*

[1] Capozzi G, Modena G. In: Patai S, editor. The Chemistry of Thiol Group: Part 2. New York: John Wiley & Sons,

[2] Reid EE. Organic Chemistry of Bivalent Sulfur. Vol. I. New York: Chemical Publishing Co. Inc.; 1958.

[3] Tarbell DS. In: Kharash N, editor. Organic Sulfur Compounds: Chapter 10. Vol. 1. New York: Pergamon Press; 1961.

[4] Wallace JG. Hydrogen Peroxide in Organic Chemistry, E. I. Wilmington, U.S.A: du Pont de Nemours and Co.;

[5] Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. 4th ed. Oxford, UK: Clarendon Press; 2007

[6] Bahorun T, Soobrattee MA, Luximon-Ramma V, Aruoma OI. Free radicals and antioxidants in cardiovascular health and disease. Internet Journal of Medical Update.

[7] Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J. Role of oxygen radicals in DNA damage and cancer incidence. Molecular and Cellular Biochemistry. 2004;**266**:37-56

[8] Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry and Cell Biology.

[9] Droge W. Free radicals in the physiological control of cell function. Physiological Reviews. 2002;**82**:47-95

[10] Willcox JK, Ash SL, Catignani GL. Antioxidants and prevention of chronic

**References**

pp. 118-126

pp. 97-102

1960

2006;**1**:1-17

2007;**39**:44-84

Inc; 1874. pp. 78-839

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using… DOI: http://dx.doi.org/10.5772/intechopen.81146*

#### **References**

*Heterocycles - Synthesis and Biological Activities*

**3. Conclusion**

(d, *J* = 8 Hz, 1H), 6.45 (s, 1H), 2.47 (s, 2H), 2.29–2.20 (m, 2H), 1.07 (s, 3H), 0.91 (s, 3H), Anal. Calcd for C22H19BrN2OS: C, 60.14; H, 4.36; Br, 18.19; N, 6.38; O, 3.64;

DMSO–*d6*): *δ* = 7.49–7.46 (m, 2H), 7.38 (d, *J* = 8 Hz, 2H), 7.23–7.07 (m, 2H), 6.74 (d, *J* = 8 Hz, 2H), 6.44 (s, 1H), 3.62 (s, 3H), 2.48 (s, 2H), 2.31–2.17 (m, 2H), 1.06 (s, 3H), 0.93 (s, 3H). Anal. Calcd for C23H22N2O2S: C, 70.74; H, 5.68; N, 7.17; O, 8.19;

mimic the *in vivo* biochemical reactions involved and corroborate the role of O2

living cells. Since the investigation has been performed at an ambient temperature in

occurring at physiological temperatures in more complex biological counterparts. A novel synthetic route has been developed for the synthesis of tetraheterocyclic benzimidazolo/benzothiazolo quinazolin-1-one ring systems using tetraethylammonium superoxide under non aqueous condition at room temperature (mild reaction condition) within 6 h. The yield of the products was obtained up to 88% without using any tedious purification process. The applicability of tetraethylammonium bromide as an inexpensive alternative to 18-crown-6 for superoxide ion

The authors are thankful to IIT(BHU),Varanasi for financial support.

**3,3–Dimethyl–12–(4-methoxyphenyl)–2,3,4,12–tetrahydro–1H–benzo[4,5]**

H NMR (500 MHz,

•<sup>−</sup> with imidazoles is able to

•<sup>−</sup>, the results may be easily correlated with those

•<sup>−</sup> in

S, 7.30. Found: C, 60.35; H, 4.49; Br, 18.37; N, 6.50; O, 3.80; S, 7.45.

**thiazolo[2,3–b]quinazolin–1–one (4o**): M.p. 87–88°C. 1

S, 8.21. Found: C, 70.89; H, 5.80; N, 7.35; O, 8.39; S, 8.40.

In conclusion, the reaction of *in situ* generated O2

generation has been extended in present report.

the presence of *in situ* generated O2

**Acknowledgements**

**Conflict of interest**

**Author details**

No conflict of interest.

Sundaram Singh\* and Savita Kumari

provided the original work is properly cited.

Indian Institute of Technology (BHU), Varanasi, UP, India

\*Address all correspondence to: sundaram.apc@itbhu.ac.in

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

**86**

[1] Capozzi G, Modena G. In: Patai S, editor. The Chemistry of Thiol Group: Part 2. New York: John Wiley & Sons, Inc; 1874. pp. 78-839

[2] Reid EE. Organic Chemistry of Bivalent Sulfur. Vol. I. New York: Chemical Publishing Co. Inc.; 1958. pp. 118-126

[3] Tarbell DS. In: Kharash N, editor. Organic Sulfur Compounds: Chapter 10. Vol. 1. New York: Pergamon Press; 1961. pp. 97-102

[4] Wallace JG. Hydrogen Peroxide in Organic Chemistry, E. I. Wilmington, U.S.A: du Pont de Nemours and Co.; 1960

[5] Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. 4th ed. Oxford, UK: Clarendon Press; 2007

[6] Bahorun T, Soobrattee MA, Luximon-Ramma V, Aruoma OI. Free radicals and antioxidants in cardiovascular health and disease. Internet Journal of Medical Update. 2006;**1**:1-17

[7] Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J. Role of oxygen radicals in DNA damage and cancer incidence. Molecular and Cellular Biochemistry. 2004;**266**:37-56

[8] Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry and Cell Biology. 2007;**39**:44-84

[9] Droge W. Free radicals in the physiological control of cell function. Physiological Reviews. 2002;**82**:47-95

[10] Willcox JK, Ash SL, Catignani GL. Antioxidants and prevention of chronic disease. Critical Reviews in Food Science and Nutrition. 2004;**44**:275-295

[11] Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiological Reviews. 2007;**87**:315-424

[12] Genestra M. Oxyl radicals, redox-sensitive signalling cascades and antioxidants. Cellular Signalling. 2007;**19**:1807-1819

[13] Halliwell B. Biochemistry of oxidative stress. Biochemical Society Transactions. 2007;**35**:1147-1150

[14] Witt A, Bergman J. Recent developments in the field of quinazoline chemistry. Current Organic Chemistry. 2003;**7**:659-677

[15] Connolly DJ, Cusack D, O'Sullivan TP, Guiry PJ. Synthesis of quinazolinones and quinazolines. Tetrahedron. 2005;**61**:10153-10202

[16] Grasso S, Micale N, Monforte A-M, Monforte P, Polimeni S, Zappala M. Synthesis and in vitro antitumour activity evaluation of 1-aryl-1H, 3H-thiazolo [4, 3-b] quinazolines. European Journal of Medicinal Chemistry. 2000;**35**:1115-1119

[17] Testard A, Picot L, Lozach O, Blairvacq M, Meijer L, Murillo L, et al. Synthesis and evaluation of the antiproliferative activity of novel thiazoloquinazolinone kinases inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry. 2005;**20**:557-568

[18] Weber L. The application of multicomponent reactions in drug discovery. Current Medicinal Chemistry. 2002;**9**:2085-2093

[19] Hulme C, Gore V. Multi-component Reactions: Emerging Chemistry in

Drug Discovery From Xylocain to Crixivan. Current Medicinal Chemistry. 2003;**10**:51-80

[20] Dömling A, Ugi I. Multicomponent reactions with isocyanides. Angewandte Chemie, International Edition. 2000;**39**:3168-3210

[21] Shaabani A, Rahmati A, Naderi S. A novel one-pot three-component reaction: Synthesis of triheterocyclic 4H-pyrimido [2, 1-b] benzazoles ring systems. Bioorganic & Medicinal Chemistry Letters. 2005;**15**:5553-5557

[22] Johne S, Herz W, Grisebach H, Kirby GW, Tamm Ch. The quinazoline alkaloids. InFortschritte der Chemie organischer Naturstoffe/Progress in the Chemistry of Organic Natural Products. Vol. 46. Wien: Springer; 1984. pp. 159-229

[23] Johne S. In: Brossi A, editor. The Alkaloids, Chemistry and Pharmacology. Vol. 29. New York: Academic; 1986. pp. 99-140

[24] Liu JF, Kaselj M, Isome Y, Ye P, Sargent K, Sprague K, et al. Design and synthesis of a quinazolinone natural product-templated library with cytotoxic activity. Journal of Combinatorial Chemistry. 2006;**8**:7-10

[25] Hattori K, Kido Y, Yamamoto H, Ishida J, Kamijo K, Murano K, et al. Rational approaches to discovery of orally active and brainpenetrable quinazolinone inhibitors of poly (ADP-ribose) polymerase. Journal of Medicinal Chemistry. 2004;**47**:4151-4154

[26] Young I, Woodside J. Antioxidants in health and disease. Journal of Clinical Pathology. 2001;**54**:176-186

[27] Chai D, Fitch DM. WO Patent 09039322 A1. March, 2009

[28] Kato F, Kimura H, Omatsu M, Yamamoto K, Miyamoto R. WO Patent 02040485. May 23, 2002

[29] McMaster B. WO Patent 03105857. December 24, 2003

[30] Shigeta S, Mori S, Baba M, Hosoya M, Mochizuki N, Chiba T, et al. Inhibitory effect of pyridobenzoazoles on orthomyxo-and paramyxovirus replication in vitro. Antiviral Chemistry and Chemotherapy. 1992;**3**:171-177

[31] Nofal ZM, Fahmy HH, Mohamed HS. Synthesis, antimicrobial and molluscicidal activities of new benzimidazole derivatives. Archives of Pharmacal Research. 2002;**25**:28-38

[32] Abdel-hafez AA. Benzimidazole condensed ring systems: New synthesis and antineoplastic activity of substituted 3, 4-dihydro-and 1, 2, 3, 4-tetrahydro-benzo [4, 5] imidazo [1, 2-a] pyrinnidine derivatives. Archives of Pharmacal Research. 2007;**30**:678-684

[33] Lunn W, Harper R, Stone R. Benzimidazo [2, 1-b] quinazolin-12-ones. New class of potent immunosuppressive compounds. Journal of Medicinal Chemistry. 1971;**14**:1069-1071

[34] Lipson VV, Desenko SM, Shirobokova MG, Borodina VV. Synthesis of 9-Aryl-6, 6-dimethyl-5, 6, 7, 9-tetrahydro-1, 2, 4-triazolo [5, 1-b] quinazolin-8 (4H) ones. Chemistry of Heterocyclic Compounds. 2003;**39**:1213-1217

[35] Lipson VV, Desenko SM, Shishkina SV, Shirobokova MG, Shishkin OV, Orlov VD. Cyclocondensation of 2-aminobenzimidazole with dimedone and its arylidene derivatives. Chemistry of Heterocyclic Compounds. 2003;**39**:1041-1047

[36] Shaabani A, Farhangi E, Rahmati A. A Rapid Combinatorial

**89**

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using…*

*DOI: http://dx.doi.org/10.5772/intechopen.81146*

Library Synthesis of Benzazolo [2, 1-b] quinazolinones and Triazolo [2, 1-b] quinazolinones. Iranian Journal of Chemistry and Chemical Engineering

(IJCCE). 2013;**32**:3-10

17; 2013. pp. 1-9

[37] Ali M, Nakisa G. A three-

component onepot procedure for the synthesis benzimidazoloquinazolinone derivatives in the presence of chitosansupported metal nanocomposite as a green and reusable catalyst. In: ECSOC-

[38] Ahmad S, Elham F, Abbas R. Synthesis of tetrahydrobenzimidazo [1, 2-b] quinazolin-1 (2H)-one and tetrahydro-1, 2, 4-triazolo [5, 1-b] quinazolin-8 (4H)-one ring systems under solvent-free conditions. Combinatorial Chemistry & High Throughput Screening. 2006;**9**:771-776

[39] Atar AB, Jeong YS, Jeong YT. Iron fluoride: The most efficient catalyst for one-pot synthesis of 4H-pyrimido

solvent-free conditions. Tetrahedron.

[2, 1-b] benzothiazoles under

[40] Heravi MM, Derikvand F, Ranjbar L. Sulfamic acid–catalyzed, three-component, one-pot synthesis of [1, 2, 4] triazolo/benzimidazolo quinazolinone derivatives. Synthetic Communications®. 2010;**40**:677-685

2014;**70**:5207-5213

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using… DOI: http://dx.doi.org/10.5772/intechopen.81146*

Library Synthesis of Benzazolo [2, 1-b] quinazolinones and Triazolo [2, 1-b] quinazolinones. Iranian Journal of Chemistry and Chemical Engineering (IJCCE). 2013;**32**:3-10

*Heterocycles - Synthesis and Biological Activities*

[28] Kato F, Kimura H, Omatsu M, Yamamoto K, Miyamoto R. WO Patent

[29] McMaster B. WO Patent 03105857.

Hosoya M, Mochizuki N, Chiba T, et al. Inhibitory effect of pyridobenzoazoles on orthomyxo-and paramyxovirus replication in vitro. Antiviral Chemistry and Chemotherapy. 1992;**3**:171-177

[31] Nofal ZM, Fahmy HH, Mohamed HS. Synthesis, antimicrobial and molluscicidal activities of new

benzimidazole derivatives. Archives of Pharmacal Research. 2002;**25**:28-38

[32] Abdel-hafez AA. Benzimidazole condensed ring systems: New synthesis and antineoplastic activity of substituted 3, 4-dihydro-and 1, 2, 3, 4-tetrahydro-benzo [4, 5] imidazo [1, 2-a] pyrinnidine derivatives. Archives of Pharmacal Research. 2007;**30**:678-684

[33] Lunn W, Harper R, Stone R. Benzimidazo [2, 1-b] quinazolin-12-ones. New class of potent immunosuppressive compounds. Journal of Medicinal Chemistry.

[34] Lipson VV, Desenko SM, Shirobokova MG, Borodina VV. Synthesis of 9-Aryl-6, 6-dimethyl-5, 6, 7, 9-tetrahydro-1, 2, 4-triazolo [5, 1-b] quinazolin-8 (4H) ones.

Chemistry of Heterocyclic Compounds.

[35] Lipson VV, Desenko SM, Shishkina

dimedone and its arylidene derivatives. Chemistry of Heterocyclic Compounds.

SV, Shirobokova MG, Shishkin OV, Orlov VD. Cyclocondensation of 2-aminobenzimidazole with

[36] Shaabani A, Farhangi E, Rahmati A. A Rapid Combinatorial

1971;**14**:1069-1071

2003;**39**:1213-1217

2003;**39**:1041-1047

[30] Shigeta S, Mori S, Baba M,

02040485. May 23, 2002

December 24, 2003

[20] Dömling A, Ugi I. Multicomponent reactions with isocyanides. Angewandte

Drug Discovery From Xylocain to Crixivan. Current Medicinal Chemistry.

Chemie, International Edition.

[21] Shaabani A, Rahmati A, Naderi S. A novel one-pot three-component reaction: Synthesis of triheterocyclic 4H-pyrimido [2, 1-b] benzazoles ring systems. Bioorganic & Medicinal Chemistry Letters. 2005;**15**:5553-5557

[22] Johne S, Herz W, Grisebach H, Kirby GW, Tamm Ch. The quinazoline alkaloids. InFortschritte der Chemie organischer Naturstoffe/Progress in the Chemistry of Organic Natural Products. Vol. 46. Wien: Springer; 1984.

[23] Johne S. In: Brossi A, editor. The Alkaloids, Chemistry and Pharmacology. Vol. 29. New York: Academic; 1986. pp. 99-140

[24] Liu JF, Kaselj M, Isome Y, Ye P, Sargent K, Sprague K, et al. Design and synthesis of a quinazolinone natural product-templated library with cytotoxic activity. Journal of Combinatorial Chemistry. 2006;**8**:7-10

[25] Hattori K, Kido Y, Yamamoto H, Ishida J, Kamijo K, Murano K, et al. Rational approaches to discovery of orally active and brainpenetrable quinazolinone inhibitors of poly (ADP-ribose) polymerase. Journal of Medicinal Chemistry.

[26] Young I, Woodside J. Antioxidants in health and disease. Journal of Clinical

[27] Chai D, Fitch DM. WO Patent

2004;**47**:4151-4154

Pathology. 2001;**54**:176-186

09039322 A1. March, 2009

2003;**10**:51-80

2000;**39**:3168-3210

pp. 159-229

**88**

[37] Ali M, Nakisa G. A threecomponent onepot procedure for the synthesis benzimidazoloquinazolinone derivatives in the presence of chitosansupported metal nanocomposite as a green and reusable catalyst. In: ECSOC-17; 2013. pp. 1-9

[38] Ahmad S, Elham F, Abbas R. Synthesis of tetrahydrobenzimidazo [1, 2-b] quinazolin-1 (2H)-one and tetrahydro-1, 2, 4-triazolo [5, 1-b] quinazolin-8 (4H)-one ring systems under solvent-free conditions. Combinatorial Chemistry & High Throughput Screening. 2006;**9**:771-776

[39] Atar AB, Jeong YS, Jeong YT. Iron fluoride: The most efficient catalyst for one-pot synthesis of 4H-pyrimido [2, 1-b] benzothiazoles under solvent-free conditions. Tetrahedron. 2014;**70**:5207-5213

[40] Heravi MM, Derikvand F, Ranjbar L. Sulfamic acid–catalyzed, three-component, one-pot synthesis of [1, 2, 4] triazolo/benzimidazolo quinazolinone derivatives. Synthetic Communications®. 2010;**40**:677-685

**91**

**Chapter 7**

**Abstract**

(benzoxazepines).

**1. Introduction**

are taken into consideration.

**2. Classification of oxygen heterocycles**

The Oxygen-Containing Fused

The oxygen-containing heterocycles are an important class of compounds in organic chemistry. These compounds are used as drugs (coumarin and oxazole), solvent (tetrahydrofuran), flavors, and fragrances (lactones). The fusion of aromatic ring to the oxygen-heterocycle will change the electron density; thereby, the physical/chemical/biological properties will alter. Also, the preparation of these fused molecules will require a different strategy/method/reaction condition. The topics covered in this chapter are the general synthetic methods and uses of fused heterocyclic compounds containing oxygen as a heteroatom. The derivatization of the primary scaffold is excluded from this chapter. Some of the fused compounds are coumarin (benzopyrans) and piclozotan

**Keywords:** heterocycles, oxygen heteroatom, fused molecules, coumarin, a flavonoid

The oxygen-containing heterocycles are an important class of compounds in organic chemistry mainly because of their natural abundance and diverse biological functions. Natural and semi-synthetic oxygen heterocyclic compounds such as Taxol [1] (anticancer), Digoxin (CHF treatment), Cyclosporine-A (immunosuppressant) and Lovastatin (hypolipidemic) are well known used as promising therapeutic compounds [2]. Kaur et al. reviewed the oxygen heterocycles wherein saturated and unsaturated compounds are considered. They discussed the classification and chemistry of each of those compounds [1]. Reports are available wherein the synthesis of natural products containing oxygen as heteroatom is reviewed by Cossy and Guérinot [2]. Also, Rowlands and Farley chaptered the book on the anion radicals from oxygen-containing heterocycles [3]. None of these reports target the oxygen-containing heterocyclic compounds where fused rings

The oxygen-containing heterocycles can be classified in several ways like the classification based on (a) the number of oxygen atoms, (b) saturation level, (c) aromaticity or (d) abundance. For the clarity of the concept, the classification

Heterocyclic Compounds

*and Nanjangud Venkatesh Anil Kumar*

*Hillemane Venkatachalam* 

#### **Chapter 7**

## The Oxygen-Containing Fused Heterocyclic Compounds

*Hillemane Venkatachalam and Nanjangud Venkatesh Anil Kumar*

#### **Abstract**

The oxygen-containing heterocycles are an important class of compounds in organic chemistry. These compounds are used as drugs (coumarin and oxazole), solvent (tetrahydrofuran), flavors, and fragrances (lactones). The fusion of aromatic ring to the oxygen-heterocycle will change the electron density; thereby, the physical/chemical/biological properties will alter. Also, the preparation of these fused molecules will require a different strategy/method/reaction condition. The topics covered in this chapter are the general synthetic methods and uses of fused heterocyclic compounds containing oxygen as a heteroatom. The derivatization of the primary scaffold is excluded from this chapter. Some of the fused compounds are coumarin (benzopyrans) and piclozotan (benzoxazepines).

**Keywords:** heterocycles, oxygen heteroatom, fused molecules, coumarin, a flavonoid

#### **1. Introduction**

The oxygen-containing heterocycles are an important class of compounds in organic chemistry mainly because of their natural abundance and diverse biological functions. Natural and semi-synthetic oxygen heterocyclic compounds such as Taxol [1] (anticancer), Digoxin (CHF treatment), Cyclosporine-A (immunosuppressant) and Lovastatin (hypolipidemic) are well known used as promising therapeutic compounds [2]. Kaur et al. reviewed the oxygen heterocycles wherein saturated and unsaturated compounds are considered. They discussed the classification and chemistry of each of those compounds [1]. Reports are available wherein the synthesis of natural products containing oxygen as heteroatom is reviewed by Cossy and Guérinot [2]. Also, Rowlands and Farley chaptered the book on the anion radicals from oxygen-containing heterocycles [3]. None of these reports target the oxygen-containing heterocyclic compounds where fused rings are taken into consideration.

#### **2. Classification of oxygen heterocycles**

The oxygen-containing heterocycles can be classified in several ways like the classification based on (a) the number of oxygen atoms, (b) saturation level, (c) aromaticity or (d) abundance. For the clarity of the concept, the classification

**Figure 1.**

*Mono-oxygen containing fused heterocyclic compounds.*

**Figure 2.**

*Di-oxygen containing fused heterocyclic compounds.*

based on a number of oxygen atoms is used. The benzene fused furan and pyrans are listed in **Figure 1**, whereas **Figure 2** represents the compounds with two oxygen atoms in the ring system.

#### **3. Synthesis of benzofurans**

#### **3.1 Mono-substituted benzofurans**

#### *3.1.1 Substitution on furan ring*

The ortho-hydroxystilbenes are cyclized in 70–90% yield in a metal-free environment using hypervalent iodine and 1 eq. of (diacetoxyiodo) benzene to get 2-substituted benzofurans [4]. The acids are converted to 2,4,6- trichloro-1,3,5-triazine esters, which are subsequently added to toluene, 2-hydroxybenzyl triphenylphosphonium bromide (1 eq.), and NEt3 and irradiated at 110°C for two cycles of 30 min to get the 2-substituted benzofurans having a chiral stereocenter adjacent to the heterocycle in 60–80% yield [5]. Pd-catalyzed cyclisation of 2-chloroaryl alkynes using KOH at 100°C for 8 h resulted in the formation of benzofurans [6]. All three reactions are as shown in **Figure 3**.

#### *3.1.2 Substitution on the benzene ring*

Also, the substituted 1-allyl-2-allyloxybenzenes cyclizes to give substituted benzofurans by isomerization followed by ring-closure metathesis reaction using 5 mol.% catalyst [7]. The homologous members of benzofurans can be prepared by 0.1 eq. of Ru-catalyzed cycloisomerization of homo- and bis-homopropargylic alcohols in presence of pyridine at 90°C for 1–6 h [8] as shown in **Figure 4**.

**93**

**3.2 Di-substituted benzofurans**

*Benzene ring substituted benzofuran.*

*Preparation of mono-substituted benzofuran.*

**Figure 3.**

**Figure 4.**

*3.2.1 Substitution on furan and benzene ring of benzofuran*

These reaction schemes are as shown in **Figure 5**.

The reaction between 1 eq. of 2-(2-hydroxyphenyl)acetonitriles with 2 eq of aryl boronic acids along with Pd(OAc)2 (5 mol.%), bpy (10 mol.%), TFA (10 eq.), with TFA as solvent heated to 80°C for 36 h resulted in benzofuran derivatives with more than 80% yield [9]. Sonogashira cross-coupling reaction of halide with terminal alkynes followed by cyclization of the resulting 2-alkynylphenols in one-pot method results in benzofuran. The method employs the t-BuOH, PdCl2- (CH3CN)2 (2 mol.%), t-BuOLi (3.6 eq.) and 2-chlorophenol (1 eq.), alkyne

(1.5 eq.) were taken in a sealed tube and heated to 110°C for 22 h to get benzofuran [10]. Reaction of N-tosylhydrazones and terminal alkyne in a ligand free environment, using 10 mol.% of CuBr and 3 eq. of Cs2CO3 at 100°C for 4 h resulted in the formation of benzofurans with 38–91% yield [11]. Reductive cyclization of 1-(2-hydroxyphenyl)-propargyl alcohols in presence of Pd(OAc)2 (5 mol.%), t-BuNC (1.2 eq.), Cs2CO3 (1.2 eq.) and MeCN as solvent gives benzofurans [12].

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

**Figure 3.**

*Heterocycles - Synthesis and Biological Activities*

*Di-oxygen containing fused heterocyclic compounds.*

*Mono-oxygen containing fused heterocyclic compounds.*

atoms in the ring system.

**3. Synthesis of benzofurans**

*3.1.1 Substitution on furan ring*

**3.1 Mono-substituted benzofurans**

*3.1.2 Substitution on the benzene ring*

based on a number of oxygen atoms is used. The benzene fused furan and pyrans are listed in **Figure 1**, whereas **Figure 2** represents the compounds with two oxygen

The ortho-hydroxystilbenes are cyclized in 70–90% yield in a metal-free environment using hypervalent iodine and 1 eq. of (diacetoxyiodo) benzene to get 2-substituted benzofurans [4]. The acids are converted to 2,4,6- trichloro-1,3,5-triazine esters, which are subsequently added to toluene, 2-hydroxybenzyl triphenylphosphonium bromide (1 eq.), and NEt3 and irradiated at 110°C for two cycles of 30 min to get the 2-substituted benzofurans having a chiral stereocenter adjacent to the heterocycle in 60–80% yield [5]. Pd-catalyzed cyclisation of 2-chloroaryl alkynes using KOH at 100°C for 8 h resulted in

the formation of benzofurans [6]. All three reactions are as shown in **Figure 3**.

Also, the substituted 1-allyl-2-allyloxybenzenes cyclizes to give substituted benzofurans by isomerization followed by ring-closure metathesis reaction using 5 mol.% catalyst [7]. The homologous members of benzofurans can be prepared by 0.1 eq. of Ru-catalyzed cycloisomerization of homo- and bis-homopropargylic alcohols in presence of pyridine at 90°C for 1–6 h [8] as shown in **Figure 4**.

**92**

**Figure 2.**

**Figure 1.**

*Preparation of mono-substituted benzofuran.*

**Figure 4.** *Benzene ring substituted benzofuran.*

#### **3.2 Di-substituted benzofurans**

#### *3.2.1 Substitution on furan and benzene ring of benzofuran*

The reaction between 1 eq. of 2-(2-hydroxyphenyl)acetonitriles with 2 eq of aryl boronic acids along with Pd(OAc)2 (5 mol.%), bpy (10 mol.%), TFA (10 eq.), with TFA as solvent heated to 80°C for 36 h resulted in benzofuran derivatives with more than 80% yield [9]. Sonogashira cross-coupling reaction of halide with terminal alkynes followed by cyclization of the resulting 2-alkynylphenols in one-pot method results in benzofuran. The method employs the t-BuOH, PdCl2- (CH3CN)2 (2 mol.%), t-BuOLi (3.6 eq.) and 2-chlorophenol (1 eq.), alkyne (1.5 eq.) were taken in a sealed tube and heated to 110°C for 22 h to get benzofuran [10]. Reaction of N-tosylhydrazones and terminal alkyne in a ligand free environment, using 10 mol.% of CuBr and 3 eq. of Cs2CO3 at 100°C for 4 h resulted in the formation of benzofurans with 38–91% yield [11]. Reductive cyclization of 1-(2-hydroxyphenyl)-propargyl alcohols in presence of Pd(OAc)2 (5 mol.%), t-BuNC (1.2 eq.), Cs2CO3 (1.2 eq.) and MeCN as solvent gives benzofurans [12]. These reaction schemes are as shown in **Figure 5**.

**Figure 6.** *Preparation of di-substituted benzofuran.*

#### *3.2.2 2,3-Substituted benzofuran*

Ring closure of 2-haloaromatic ketones (1 eq.) in presence of K3PO4 (1.5 eq.), CuI (10 mol.%) and DMF at 105°C for 12–16 h results in di-substituted benzofurans [13]. The good yield coupled with atom economy was achieved, when o-alkynyl

**95**

**Figure 8.**

*Substituted benzofuran carbaldehydes.*

**Figure 7.**

*Substituted benzofurans.*

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

schemes are as shown in **Figure 6**.

phenyl acetals are cyclized using PtCl2 (2 mol.%), olefin (8 mol.%) in tolene at 30°C [14]. Cyclization of o-iodoanisoles and terminal alkynes under mild conditions using an electrophile (EX like PhSeCl or p-O2NC6H4SCl) (1.5 eq.), DCM at room temperature for 2–6 h yields 2,3-disubstituted benzofurans [15]. These reaction

Selective dehydrative C—H alkylation reaction of alkenes with alcohols using [(C6H6)(PCy3)(CO)RuH]BF4, cyclopentene, toluene at 100°C for 6–12 h results in 2,3-substituted benzofurans [16]. O-Arylhydroxylamine hydrochloride (1 eq.) with cyclic or acyclic ketones (1 eq.) in the presence of methanesulfonic acid (2 eq.), THF at 60°C for 2–24 h yields benzofurans in 40–90% yield [17]. Ketones (1 eq.) on treatment with Grignard reagents (3 eq.), benzofurans are formed, in a regioselective manner via [1,2]-aryl migration [18]. These reactions are depicted in **Figure 7**.

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

*Heterocycles - Synthesis and Biological Activities*

**94**

**Figure 6.**

**Figure 5.**

*Di-substituted benzofurans.*

*3.2.2 2,3-Substituted benzofuran*

*Preparation of di-substituted benzofuran.*

Ring closure of 2-haloaromatic ketones (1 eq.) in presence of K3PO4 (1.5 eq.), CuI (10 mol.%) and DMF at 105°C for 12–16 h results in di-substituted benzofurans [13]. The good yield coupled with atom economy was achieved, when o-alkynyl

phenyl acetals are cyclized using PtCl2 (2 mol.%), olefin (8 mol.%) in tolene at 30°C [14]. Cyclization of o-iodoanisoles and terminal alkynes under mild conditions using an electrophile (EX like PhSeCl or p-O2NC6H4SCl) (1.5 eq.), DCM at room temperature for 2–6 h yields 2,3-disubstituted benzofurans [15]. These reaction schemes are as shown in **Figure 6**.

Selective dehydrative C—H alkylation reaction of alkenes with alcohols using [(C6H6)(PCy3)(CO)RuH]BF4, cyclopentene, toluene at 100°C for 6–12 h results in 2,3-substituted benzofurans [16]. O-Arylhydroxylamine hydrochloride (1 eq.) with cyclic or acyclic ketones (1 eq.) in the presence of methanesulfonic acid (2 eq.), THF at 60°C for 2–24 h yields benzofurans in 40–90% yield [17]. Ketones (1 eq.) on treatment with Grignard reagents (3 eq.), benzofurans are formed, in a regioselective manner via [1,2]-aryl migration [18]. These reactions are depicted in **Figure 7**.

**Figure 7.** *Substituted benzofurans.*

**Figure 8.** *Substituted benzofuran carbaldehydes.*

Base-catalyzed, the condensation of o-hydroxyphenones with 1,1-dichloroethylene, gives substituted benzofuran carbaldehydes [19].

Similarly, o-cinnamyl phenols, on oxidative cyclisation, results in 2-benzyl benzofurans [20], while o-alkylphenols, on annulative reaction, gives 3-aminobenzofurans [21] (**Figure 8**).

#### **4. Synthesis of benzofuranones**

Alkenylphenols and phenyl formate reacts to give benzofuranones [22], while phenylacetic acids undergo cyclisation to give benzofuranones [23] (**Figure 9**).

**Figure 9.** *Synthesis of benzofuranones.*

#### **5. Synthesis of dibenzofurans**

Iododiaryl ether cyclizes under mild conditions to yield dibenzofurans [24]. Ortho-diazonium slats of diaryl ethers undergo intramolecular cyclisation,

**97**

**Figure 12.**

**Figure 11.**

*Coumarin synthesis using phenol derivatives.*

*Coumarin synthesis using benzaldehyde derivatives.*

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

3-aryl-4-methyl-coumarins) [32] (**Figure 12**).

**6. Synthesis of coumarins**

resulting in dibenzofurans [25]. Cross-coupling of 6-diazo-2-cyclohexenones and

Phenols react with beta-keto esters to give coumarins [27]. If phenolic acetates are used, then, acrylates are used [28]. Aromatic alkynoate undergoes cyclisation

Substituted 2-hydroxybenzaldehydes react with phenylacetic acids resulting in substituted 3-aryl coumarins [30]. With dialkyl acetylenedicarboxylate, 2-hydroxybenzaldehydes gives 4-carboxyalkyl-8-formyl coumarins [31]. 2-Hydroxybenzaldehydes (or 2-hydroxybenzaldehydes) cyclizes with aryl acetic acids to give 3-aryl coumarins (or

ortho-haloiodobenzenes gives substituted dibenzofuran [26] (**Figure 10**).

with aldehydes to form 3-acyl-4-arylcoumarins [29] (**Figure 11**).

**Figure 10.** *Mono substituted dibenzofurans.*

resulting in dibenzofurans [25]. Cross-coupling of 6-diazo-2-cyclohexenones and ortho-haloiodobenzenes gives substituted dibenzofuran [26] (**Figure 10**).

### **6. Synthesis of coumarins**

*Heterocycles - Synthesis and Biological Activities*

**4. Synthesis of benzofuranones**

**5. Synthesis of dibenzofurans**

[21] (**Figure 8**).

gives substituted benzofuran carbaldehydes [19].

Base-catalyzed, the condensation of o-hydroxyphenones with 1,1-dichloroethylene,

Similarly, o-cinnamyl phenols, on oxidative cyclisation, results in 2-benzyl benzofurans [20], while o-alkylphenols, on annulative reaction, gives 3-aminobenzofurans

Alkenylphenols and phenyl formate reacts to give benzofuranones [22], while phenylacetic acids undergo cyclisation to give benzofuranones [23] (**Figure 9**).

Iododiaryl ether cyclizes under mild conditions to yield dibenzofurans [24].

Ortho-diazonium slats of diaryl ethers undergo intramolecular cyclisation,

**96**

**Figure 10.**

**Figure 9.**

*Synthesis of benzofuranones.*

*Mono substituted dibenzofurans.*

Phenols react with beta-keto esters to give coumarins [27]. If phenolic acetates are used, then, acrylates are used [28]. Aromatic alkynoate undergoes cyclisation with aldehydes to form 3-acyl-4-arylcoumarins [29] (**Figure 11**).

Substituted 2-hydroxybenzaldehydes react with phenylacetic acids resulting in substituted 3-aryl coumarins [30]. With dialkyl acetylenedicarboxylate, 2-hydroxybenzaldehydes gives 4-carboxyalkyl-8-formyl coumarins [31]. 2-Hydroxybenzaldehydes (or 2-hydroxybenzaldehydes) cyclizes with aryl acetic acids to give 3-aryl coumarins (or 3-aryl-4-methyl-coumarins) [32] (**Figure 12**).

**Figure 11.** *Coumarin synthesis using phenol derivatives.*

**Figure 12.** *Coumarin synthesis using benzaldehyde derivatives.*

#### **7. Synthesis of isocoumarins**

Bromoalkynes reacts with benzoic acid and produces 3-substituted isocoumarins [33]. o-Halobenzoic acids and 1,3-diketones reacts to give 3-substituted isocoumarins [34]. 2-Halobenzoates and ketones react to give the same product [35]. o-Halobenzoic acids add to alkynes resulting in isocoumarin derivatives [36] (**Figure 13**).

**Figure 13.** *Synthesis of isocoumarins.*

#### **8. Synthesis of flavones and flavonols**

#### **8.1 Baker-Venkataraman rearrangement**

The chemical reaction between 2-hydroxyacetophenone and acid chloride in the presence of base yields 1,3-diketone which undergo rearrangement and

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*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

concomitant cyclisation to produce flavone [37]. This reaction is often used to

In this method, chalcone (1,3-diaryl-2-propen-1-one) is produced by condensing 2-hydroxyacetophenone with an aryl aldehyde in alkaline medium (Claisen-Schmidt condensation) followed by oxidative cyclisation of chalcone to get

A mixture of acetophenone and aromatic aldehyde when exposed to Microwave irradiation, 2-phenyl γ-benzopyrones are obtained [39]. The same compound can

In this chapter, the synthesis of fused heterocyclic compounds having oxygen as heteroatom is considered. The care is taken not to consider the reactions, where the reactions of the compounds leading to derivatizations are not included.

synthesize chromones and flavones (**Figure 14**).

be prepared by cyclizing 1,3-diaryl propanediones (**Figure 16**).

**8.2 Algar-Flynn-Oyamada synthesis**

*Preparation of 2-phenyl γ-benzopyrones.*

flavone [38] (**Figure 15**).

**9. Conclusions**

**Figure 15.**

**Figure 16.**

*Synthesis of flavone (from chalcone).*

**Figure 14.** *Synthesis of flavone (from 1,3-diketone).*

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

**Figure 15.** *Synthesis of flavone (from chalcone).*

*Heterocycles - Synthesis and Biological Activities*

**8. Synthesis of flavones and flavonols**

**8.1 Baker-Venkataraman rearrangement**

Bromoalkynes reacts with benzoic acid and produces 3-substituted isocoumarins [33]. o-Halobenzoic acids and 1,3-diketones reacts to give 3-substituted isocoumarins [34]. 2-Halobenzoates and ketones react to give the same product [35]. o-Halobenzoic

The chemical reaction between 2-hydroxyacetophenone and acid chloride in the presence of base yields 1,3-diketone which undergo rearrangement and

acids add to alkynes resulting in isocoumarin derivatives [36] (**Figure 13**).

**7. Synthesis of isocoumarins**

**98**

**Figure 14.**

*Synthesis of flavone (from 1,3-diketone).*

**Figure 13.**

*Synthesis of isocoumarins.*

**Figure 16.** *Preparation of 2-phenyl γ-benzopyrones.*

concomitant cyclisation to produce flavone [37]. This reaction is often used to synthesize chromones and flavones (**Figure 14**).

#### **8.2 Algar-Flynn-Oyamada synthesis**

In this method, chalcone (1,3-diaryl-2-propen-1-one) is produced by condensing 2-hydroxyacetophenone with an aryl aldehyde in alkaline medium (Claisen-Schmidt condensation) followed by oxidative cyclisation of chalcone to get flavone [38] (**Figure 15**).

A mixture of acetophenone and aromatic aldehyde when exposed to Microwave irradiation, 2-phenyl γ-benzopyrones are obtained [39]. The same compound can be prepared by cyclizing 1,3-diaryl propanediones (**Figure 16**).

#### **9. Conclusions**

In this chapter, the synthesis of fused heterocyclic compounds having oxygen as heteroatom is considered. The care is taken not to consider the reactions, where the reactions of the compounds leading to derivatizations are not included. Benzofurans, benzofuranones, dibenzofurans, coumarins, isocoumarins, chromones, and flavones are the fused heterocyclic compounds considered in this chapter. Also, the reactions are indicative and not the detailed reaction conditions, and appropriate reagents are not included in this chapter.

### **Conflict of interest**

No conflict of interest from both the authors.

### **Author details**

Hillemane Venkatachalam and Nanjangud Venkatesh Anil Kumar\* Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, India

\*Address all correspondence to: nv.anil@manipal.edu

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**101**

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

> aryl ketones and 2-arylbenzofurans. Synthesis. 2013;**45**(16):2241-2244

Hydroxyterphenylphoshine−palladium catalyst for benzo[b]furan synthesis from 2-chlorophenols. Bifunctional ligand strategy for cross-coupling of chloroarenes. The Journal of Organic Chemistry. 2010;**75**(15):5340-5342

[11] Zhou L et al. CuBr-catalyzed coupling of N-tosylhydrazones and terminal alkynes: Synthesis of benzofurans and indoles. Organic Letters. 2011;**13**(5):968-971

[12] Rajesh M et al. Pd-catalyzed isocyanide assisted reductive cyclization of 1-(2-hydroxyphenyl) propargyl alcohols for 2-alkyl/benzyl benzofurans and their useful oxidative derivatization. The Journal of Organic Chemistry. 2015;**80**(24):12311-12320

[13] Chen C-Y, Dormer PG. Synthesis of benzo[b]furans via CuI-catalyzed ring closure. The Journal of Organic Chemistry. 2005;**70**(17):6964-6967

[14] Nakamura I, Mizushima Y, Yamamoto Y. Synthesis of 2,3-disubstituted benzofurans by platinum−olefin-catalyzed

o-alkynylphenyl acetals. Journal of the American Chemical Society.

[15] Yue D, Yao T, Larock RC. Synthesis of 2,3-disubstituted benzo[b]furans by the palladium-catalyzed coupling of o-iodoanisoles and terminal alkynes, followed by electrophilic cyclization. The Journal of Organic Chemistry.

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[10] Wang J-R, Manabe K.

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[2] Cossy J, Guérinot A. Natural products containing oxygen heterocycles—Synthetic advances between 1990 and 2015. Advances

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*Heterocycles - Synthesis and Biological Activities*

**Conflict of interest**

and appropriate reagents are not included in this chapter.

No conflict of interest from both the authors.

Hillemane Venkatachalam and Nanjangud Venkatesh Anil Kumar\*

\*Address all correspondence to: nv.anil@manipal.edu

Department of Chemistry, Manipal Institute of Technology, Manipal Academy of

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Benzofurans, benzofuranones, dibenzofurans, coumarins, isocoumarins, chromones, and flavones are the fused heterocyclic compounds considered in this chapter. Also, the reactions are indicative and not the detailed reaction conditions,

**100**

**Author details**

Higher Education, Manipal, India

provided the original work is properly cited.

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[31] Majumdar K et al. Aromatic electrophilic substitution vs. intramolecular Wittig reaction: Vinyltriphenylphosphonium salt mediated synthesis of 4-carboxyalkyl-

8-formyl coumarins. Synlett. 2011;**2011**(05):694-698

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mediated synthesis of 3-aryl-substituted and 3,4-disubstituted coumarins. Synlett. 2017;**28**(07):825-830

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2012;**134**(17):7325-7328

2012;**14**(5):1298-1301

2011;**13**(9):2395-2397

2014;**16**(1):186-189

[20] Rehan M et al. Synthesis of functionalized benzo[b]furans via oxidative cyclization of o-cinnamyl phenols. The Journal of Organic Chemistry. 2017;**82**(7):3411-3424

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[22] Wang H et al. A palladiumcatalyzed regioselective

hydroesterification of alkenylphenols to lactones with phenyl formate as CO source. Organic Letters.

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2013;**135**(4):1236-1239

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Section 2

Synthetic and Biological

Activity Section

### Section 2
