Synthetic and Biological Activity Section

**107**

**Chapter 8**

**Abstract**

**1. Introduction**

Derivatives

Synthesis and Anticancer

Evaluation of Benzenesulfonamide

*Dattatraya Navnath Pansare and Rohini Narayan Shelke*

A highly efficient protocol was developed for the synthesis of 3-(indoline-1 carbonyl)-N-(substituted) benzene sulfonamide analogs with excellent yields. The new 3-(indoline-1-carbonyl)-N-(substituted) benzene sulfonamide derivatives (4a-g and 5a-g) were evaluated *in vitro* anticancer activity against a series of different cell lines like A549 (lung cancer cell), HeLa (cervical), MCF-7 (breast cancer cell) and Du-145 (prostate cancer cell) respectively. The results of the anticancer activity data revealed that most of the tested compounds showed IC50 values from 1.98 to 9.12 μM in different cell lines. Compounds 4b, 4d, 5d, and 5g were the most

potent, with IC50 values ranging from 1.98 to 2.72 μM in different cell lines.

Antibiotic resistant bacteria are rapidly emerging worldwide [1]. The various biological active heterocyclic compounds, the indole derivatives are the key structural feature commonly found in natural products [2, 3] and bioactive molecules, such as tryptophan [4], tryptamine [5], and auxin [6]. Furthermore, it has been reported that sharing of the indole 3-carbon in the formation of spiroindoline derivatives highly enhances biological activity [7]. Moreover, some of the compounds containing benzenesulfonamide moiety also show broad spectrum biological properties such as elastase inhibitors [8], carbonic anhydrase inhibitors [9], clostridium histolyticum collogenase inhibitors [10] as well as herbicides and plant growth regulators [11]. Sulfonamides are common motifs in many drugs and medicinal compounds and play an important role in their bioactivity since the development of sulfa antibiotics in the 1930s [12]. Common drugs such as glibenclamide [13], sultiame [14], and COX-II inhibitors Piroxicam [15], Ampiroxicam [16], and Celecoxib [17] containing a sulfonyl moiety, which displays potential activity across a variety of biological targets. The sulfonamides are organic sulfur compounds which have attracted the attention for their better pharmacological activity [18–20]. It is interesting to note that the sulfonamide containing moiety is known to have some biological and pharmaceutical properties, such as, antitumor, antibacterial, thrombin

In view of the above considerations, in continuation of our previous work on triazoles, pyrimidine, thiazoles and thiazolidinones of pharmaceutical interest [24–30] we report here on the synthesis and anticancer activity of new 3-(indoline-

**Keywords:** indoline, sulfonamide, anticancer

inhibition, and antifungal activities [21–23].

1-carbonyl)-N-(substituted) benzene sulfonamide analogs.

#### **Chapter 8**

## Synthesis and Anticancer Evaluation of Benzenesulfonamide Derivatives

*Dattatraya Navnath Pansare and Rohini Narayan Shelke*

#### **Abstract**

A highly efficient protocol was developed for the synthesis of 3-(indoline-1 carbonyl)-N-(substituted) benzene sulfonamide analogs with excellent yields. The new 3-(indoline-1-carbonyl)-N-(substituted) benzene sulfonamide derivatives (4a-g and 5a-g) were evaluated *in vitro* anticancer activity against a series of different cell lines like A549 (lung cancer cell), HeLa (cervical), MCF-7 (breast cancer cell) and Du-145 (prostate cancer cell) respectively. The results of the anticancer activity data revealed that most of the tested compounds showed IC50 values from 1.98 to 9.12 μM in different cell lines. Compounds 4b, 4d, 5d, and 5g were the most potent, with IC50 values ranging from 1.98 to 2.72 μM in different cell lines.

**Keywords:** indoline, sulfonamide, anticancer

#### **1. Introduction**

Antibiotic resistant bacteria are rapidly emerging worldwide [1]. The various biological active heterocyclic compounds, the indole derivatives are the key structural feature commonly found in natural products [2, 3] and bioactive molecules, such as tryptophan [4], tryptamine [5], and auxin [6]. Furthermore, it has been reported that sharing of the indole 3-carbon in the formation of spiroindoline derivatives highly enhances biological activity [7]. Moreover, some of the compounds containing benzenesulfonamide moiety also show broad spectrum biological properties such as elastase inhibitors [8], carbonic anhydrase inhibitors [9], clostridium histolyticum collogenase inhibitors [10] as well as herbicides and plant growth regulators [11]. Sulfonamides are common motifs in many drugs and medicinal compounds and play an important role in their bioactivity since the development of sulfa antibiotics in the 1930s [12]. Common drugs such as glibenclamide [13], sultiame [14], and COX-II inhibitors Piroxicam [15], Ampiroxicam [16], and Celecoxib [17] containing a sulfonyl moiety, which displays potential activity across a variety of biological targets. The sulfonamides are organic sulfur compounds which have attracted the attention for their better pharmacological activity [18–20]. It is interesting to note that the sulfonamide containing moiety is known to have some biological and pharmaceutical properties, such as, antitumor, antibacterial, thrombin inhibition, and antifungal activities [21–23].

In view of the above considerations, in continuation of our previous work on triazoles, pyrimidine, thiazoles and thiazolidinones of pharmaceutical interest [24–30] we report here on the synthesis and anticancer activity of new 3-(indoline-1-carbonyl)-N-(substituted) benzene sulfonamide analogs.

#### **2. Results and discussion**

#### **2.1 Chemistry**

The aim of this work was to design and synthesize a novel series of benzenesulfonamide incorporating biologically active indoline moieties to evaluate their anticancer activity. We have synthesized new derivatives containing sulfonamide linkage in frame work. The synthetic methods adopted for the preparation of the N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide derivatives (**5a-g)** in **Figure 1**. We herein report the synthesis of new substituted sulfonamide derivatives with the aim of investigating their anticancer activity (**Table 2**). The synthetic methods adopted for the preparation of the title compounds (**5a-g)** are presented below. We have tried to develop simplified reaction conditions for all the steps by avoiding costly reagents, tedious purifications and longer reactions times, we have screened peptide coupling condition in **Table 1** to obtain better yield, good purity, shorter reaction time, avoiding costly reagents and mainly reproducibility of yields.

For synthesis of compound **2** was done by using **1** treated with sulfonyl chloride at 0°C in DCM for 30 min and at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the obtained gummy material was washed with excess of n-hexane. The material was crystallized using 20% ethyl acetate: n-hexane mixture, no purification was required and the pure compound is obtained as yellow solid. This was used further used for sulfonamide reaction.

**109**

ates **4a-g** yield up to 80–85%.

*Optimization of peptide coupling reaction (5a-g).*

**Table 1.**

*Synthesis and Anticancer Evaluation of Benzenesulfonamide Derivatives*

HOBt (1.5 equiv.)

HOBt (1.5 equiv.)

**Sr. no. Coupling reagent Base Solvent Time** 

1. HATU (1.1 equiv.) TEA (1.2 equiv.) DMF 14 57 2. HATU (1.1 equiv.) DIPEA (1.2 equiv.) DMF 14 55 3. PyBOP (1.1 equiv.) TEA (1.2 equiv.) THF 14 45 4. PyBOP (1.1 equiv.) DIPEA (1.2 equiv.) THF 14 50 5. EDCI (1.5 equiv.) TEA (2.5 equiv.) DMF 14 62

6. EDCI (1.5 equiv.) DIPEA (2.5 equiv.) DMF 14 72

7. EDCI (1.5 equiv.) TEA (4 equiv.) DMF 14 78 8. HOBt (1.5 equiv.) DIPEA (4 equiv.) DMF 14 67 9. T3P (1.2 equiv.) TEA (2.5 equiv.) DCM 10 50 10. T3P (1.2 equiv.) DIPEA (2.5 equiv.) DCM 10 60 11. EDCI (1.5 equiv.) DIPEA (2.5 equiv.) DCM 10 95

Acid (1 equiv.) and indoline (1.2 equiv.)

**(h)**

**Yield (%)**

For the synthesis of compounds from **3a-g** by sulfonamide coupling, different substituted amines were coupled with **2** in presence of pyridine as base and DCM as solvent at room temperature for 4 h. The reaction mass was treated with cold 2N aqueous HCl and stirred for 30 min., the solid precipitates out in most of cases which was filtered and washed with cold diethyl ether and cold pentane, all the intermediates obtained were white solids. For intermediates **3a-g** the reaction yield was 85–95%. For synthesis of **4a-4g** requires hydrolysis of **3a-g** using lithium hydroxide, tetrahydrofuran and water at room temperature for 10 h. Work up of reactions were modified, and wash in basic conditions and later acidifying it to get desired product as white solids with required purity. The acids obtained were in pure state so that it can be directly used for next amide coupling with indoline. All reaction intermedi-

For synthesis of **5a-g** we have done series of screenings by varying different coupling reagents, different bases, solvents and time. We have varied the equivalents of reagents and bases used to get better yield and purity by avoiding column purifications. The results of screenings are explained in **Table 1**. In entry 1 and 2 we have used 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) as coupling reagent and DMF as solvent we have varied bases triethylamine and diisopropylethylamine after 14 h we got product 57 and 55% respectively. In entries 3 and 4 we have used benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) as coupling reagent and THF as solvent and TEA and DIPEA as base to obtain yields 45 and 50% respectively. In entries 5, 6, 7, and 8 we have used the EDCI and hydroxybenzotriazole (HOBt) as coupling reagents with DMF as solvent along with TEA and DIPEA as base in entries 5 and 6 we have used 2.5 equiv. of base and in entries 7 and 8 we have increased base as 4 equiv. for 14 h. The yields obtained are 62, 72, 78, and 67% respectively. Same results like entry 1 and 2 are obtained in entry 9 and 10 when we used propylphosphonic anhydride (T3P) as coupling reagent and TEA and DIPEA as bases in DCM to get 50 and 60% yield respectively. In entry 11 it was observed that when EDCI (1.5 equiv.) when used along with DIPEA (2.5 equiv.) in DCM the yields was 95%, highlighted bold in **Table 1**. Work up requires extraction, and later on washing with 2N aqueous hydrochloric acid (HCl) to

*DOI: http://dx.doi.org/10.5772/intechopen.88139*

**Figure 1.**

*Synthesis of N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide. Reagents and conditions: (a) sulfonyl chloride, dichloromethane (DCM) 0°C-rt; (b) substituted amine, pyridine, DCM, 0°C-rt; (c) lithium hydroxide (LiOH), tetrahydrofuran (THF), water (H2O), rt.; (d) indoline, 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide (EDCI), diisopropylethylamine (DIPEA), DCM, rt.*


*Synthesis and Anticancer Evaluation of Benzenesulfonamide Derivatives DOI: http://dx.doi.org/10.5772/intechopen.88139*

#### **Table 1.**

*Heterocycles - Synthesis and Biological Activities*

The aim of this work was to design and synthesize a novel series of benzenesulfonamide incorporating biologically active indoline moieties to evaluate their anticancer activity. We have synthesized new derivatives containing sulfonamide linkage in frame work. The synthetic methods adopted for the preparation of the N-(substituted

For synthesis of compound **2** was done by using **1** treated with sulfonyl chloride at 0°C in DCM for 30 min and at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the obtained gummy material was washed with excess of n-hexane. The material was crystallized using 20% ethyl acetate: n-hexane mixture, no purification was required and the pure compound is obtained as yellow solid. This was used further used for sulfonamide reaction.

*Synthesis of N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide. Reagents and conditions: (a) sulfonyl chloride, dichloromethane (DCM) 0°C-rt; (b) substituted amine, pyridine, DCM, 0°C-rt; (c) lithium hydroxide (LiOH), tetrahydrofuran (THF), water (H2O), rt.; (d) indoline, 1-ethyl-3-(3-*

*dimethylaminopropyl)carbodiimide (EDCI), diisopropylethylamine (DIPEA), DCM, rt.*

phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide derivatives (**5a-g)** in **Figure 1**. We herein report the synthesis of new substituted sulfonamide derivatives with the aim of investigating their anticancer activity (**Table 2**). The synthetic methods adopted for the preparation of the title compounds (**5a-g)** are presented below. We have tried to develop simplified reaction conditions for all the steps by avoiding costly reagents, tedious purifications and longer reactions times, we have screened peptide coupling condition in **Table 1** to obtain better yield, good purity, shorter reac-

tion time, avoiding costly reagents and mainly reproducibility of yields.

**2. Results and discussion**

**2.1 Chemistry**

**108**

**Figure 1.**

*Optimization of peptide coupling reaction (5a-g).*

For the synthesis of compounds from **3a-g** by sulfonamide coupling, different substituted amines were coupled with **2** in presence of pyridine as base and DCM as solvent at room temperature for 4 h. The reaction mass was treated with cold 2N aqueous HCl and stirred for 30 min., the solid precipitates out in most of cases which was filtered and washed with cold diethyl ether and cold pentane, all the intermediates obtained were white solids. For intermediates **3a-g** the reaction yield was 85–95%.

For synthesis of **4a-4g** requires hydrolysis of **3a-g** using lithium hydroxide, tetrahydrofuran and water at room temperature for 10 h. Work up of reactions were modified, and wash in basic conditions and later acidifying it to get desired product as white solids with required purity. The acids obtained were in pure state so that it can be directly used for next amide coupling with indoline. All reaction intermediates **4a-g** yield up to 80–85%.

For synthesis of **5a-g** we have done series of screenings by varying different coupling reagents, different bases, solvents and time. We have varied the equivalents of reagents and bases used to get better yield and purity by avoiding column purifications. The results of screenings are explained in **Table 1**. In entry 1 and 2 we have used 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) as coupling reagent and DMF as solvent we have varied bases triethylamine and diisopropylethylamine after 14 h we got product 57 and 55% respectively. In entries 3 and 4 we have used benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) as coupling reagent and THF as solvent and TEA and DIPEA as base to obtain yields 45 and 50% respectively. In entries 5, 6, 7, and 8 we have used the EDCI and hydroxybenzotriazole (HOBt) as coupling reagents with DMF as solvent along with TEA and DIPEA as base in entries 5 and 6 we have used 2.5 equiv. of base and in entries 7 and 8 we have increased base as 4 equiv. for 14 h. The yields obtained are 62, 72, 78, and 67% respectively. Same results like entry 1 and 2 are obtained in entry 9 and 10 when we used propylphosphonic anhydride (T3P) as coupling reagent and TEA and DIPEA as bases in DCM to get 50 and 60% yield respectively. In entry 11 it was observed that when EDCI (1.5 equiv.) when used along with DIPEA (2.5 equiv.) in DCM the yields was 95%, highlighted bold in **Table 1**. Work up requires extraction, and later on washing with 2N aqueous hydrochloric acid (HCl) to

obtain solid compounds. Which was washed with 5% DCM: hexane, cold diethyl ether and cold pentane gives the desired compounds in yield highest yields and with 95% and above purity for **5a-g**. We have not used HOBt in entry 11 and 90% yield obtain after 10 h only. The advantage of peptide coupling screenings are no need of column chromatography, no costly reagents required, no prep purification required. All obtained compounds are with 95% and above purity and are directly used for anticancer testing.

#### **2.2 Biological evaluation: anticancer activity**

The synthesized compounds were evaluated for their *in vitro* anticancer activity against human lung cancer cell line (A549), cervical (HeLa) cancer cell line, breast cancer cell line (MCF-7) and prostate cell line (DU-145) using 5-fluorouracil as reference drug [31].

5-Flourouracil is used for anal, breast, colorectal, esophageal, stomach, pancreatic and skin cancers mainly. The response parameter calculated was the IC50 value, which corresponds to the concentration required for 50% inhibition of cell viability. The results are presented in **Table 2**, where all compounds exhibit moderate to good activity compared to 5-fluorouracil as positive control. In the case of the human lung cancer cell line (A549) compounds **4a, 4b, 4d, 4f, 5d,** and **5g** were the most potent, with IC50 values ranging from 1.98 to 2.82 μM. On the HeLa cell line the compounds which showed potent activity were **4b, 4d, 5d,** and **5g** (IC50 = 1.99–2.92 μM). In case of the MCF-7 breast cancer cell line, the potent compounds were **4d, 5d,** and **5g** with IC50 activity of 2.12–2.52 μM. Lower activity was observed for the synthesized compounds on the Du-145 prostate cancer cell line, where the most potent candidates were compounds **5g** with IC50 activity in the range of 2.12 μM. Generally, the lung


#### **Table 2.**

In vitro *anticancer screening of the synthesized compounds against four cell lines, data are expressed as IC50 (μM) SD (n = 3).*

**111**

solids. Yield 1.6 g (90%).

54 g (81%).

*Synthesis and Anticancer Evaluation of Benzenesulfonamide Derivatives*

(A549) and cervical (HeLa) cancer cell lines were the most sensitive to the synthesized compounds. With regard to broad spectrum anticancer activity, close examination of the data presented in **Table 2**, reveals that compounds **4b, 4d,** and **5g** were the most active, showing effectiveness toward the four cell lines. The structure activity relationship (SAR) can be explained on the basis of substitutions on both the aromatic rings less hindered substitution like methyl and ethyl on ortho and para position of rings increases the anticancer activity in all four cell lines, interestingly ortho triflouromethyl and indoline group decreases the anticancer activity and despite steric hindrance **4b**, **4d, 5d,** and **5g** shows promising activity because of electron donating tendency. Most of the compounds show promising anticancer activity with electron donating groups

**2.3 General experimental procedure for the synthesis of N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide (5a-g)**

*2.3.2 Step-2: preparation of ethyl 3-(N-(o-tolyl)sulfamoyl)benzoate (3a-g)*

*2.3.3 Step-3: preparation of 3-(N-(o-tolyl)sulfamoyl)benzoic acid (4a-g)*

To a stirred solution of ethyl 3-(N-(o-tolyl)sulfamoyl)benzoate (**3a-g)** (2 g, 5.40 mmol) in THF (10 ml) added water (2 ml), and lithium hydroxide (0.377 g, 18.2 mmol) and stirred reaction mixture for 4 h. Progress reaction was monitored by TLC and LCMS. After the completion of reaction evaporate reaction mixture under reduced pressure to obtain gummy material. Added 10 ml of water in it and extracted it with diethyl ether (10 ml). Collected aqueous layer and adjust its pH to 4 by using 6N aqueous HCl. Precipitation occurs stirred it for 30 min. Filtered the obtained solid and wash it with excess of water, cold diethyl ether (10 ml) and cold pentane (10 ml) to obtain desired 3-(N-(o-tolyl)sulfamoyl)benzoic acid **4a** as white

To a stirred solution of ethyl benzoate (10 g, 67 mmol) in DCM (25 mL). RM was cooled to 0°C and chloro sulfonic acid (9 g, 73 mmol) was added drop wise and stirred for 1 h at same temperature followed by stirring at room temperature for 1 h. After completion of reaction, evaporate reaction mixture under reduced pressure and obtained gummy material is washed with excess of hexane and it is crystalized from 20% ethyl acetate: hexane mixture to obtain white solid as ethyl 3-(chlorosulfonyl)benzoate **(2)** which is used further for sulfonamide coupling reaction. Yield

To a stirred solution of ethyl 3-(chlorosulfonyl)benzoate **(2)** (3 g, 10.1 mmol) in DCM (5 ml) was added pyridine (5 ml) the mixture was stirred at room temperature for 10 min. RM was cooled to 0°C and 2-methyl aniline (1.6 g, 15.16 mmol) was added drop wise followed by stirring at room temperature for 3 h. The reaction was monitored by TLC and LCMS, after completion of reaction poured reaction mass on cold 2N aqueous HCl (10 ml) and stirred RM it for 30 min. Precipitation formed in RM. Filtered the obtained solid and wash it with excess of water and cold diethyl ether (10 ml) and cold pentane (10 ml) to obtain ethyl 3-(N-(o-tolyl)sulfamoyl)

*2.3.1 Step-1: preparation of ethyl 3-(chlorosulfonyl)benzoate (2)*

*DOI: http://dx.doi.org/10.5772/intechopen.88139*

on the ring than electron withdrawing groups.

benzoate **2** as white solid. Yield 2.8 g (90%).

*Synthesis and Anticancer Evaluation of Benzenesulfonamide Derivatives DOI: http://dx.doi.org/10.5772/intechopen.88139*

*Heterocycles - Synthesis and Biological Activities*

**2.2 Biological evaluation: anticancer activity**

reference drug [31].

**Compound A549 (lung** 

**cancer cell)**

obtain solid compounds. Which was washed with 5% DCM: hexane, cold diethyl ether and cold pentane gives the desired compounds in yield highest yields and with 95% and above purity for **5a-g**. We have not used HOBt in entry 11 and 90% yield obtain after 10 h only. The advantage of peptide coupling screenings are no need of column chromatography, no costly reagents required, no prep purification required. All obtained compounds are with 95% and above purity and are directly used for anticancer testing.

The synthesized compounds were evaluated for their *in vitro* anticancer activity against human lung cancer cell line (A549), cervical (HeLa) cancer cell line, breast cancer cell line (MCF-7) and prostate cell line (DU-145) using 5-fluorouracil as

5-Flourouracil is used for anal, breast, colorectal, esophageal, stomach, pancreatic and skin cancers mainly. The response parameter calculated was the IC50 value, which corresponds to the concentration required for 50% inhibition of cell viability. The results are presented in **Table 2**, where all compounds exhibit moderate to good activity compared to 5-fluorouracil as positive control. In the case of the human lung cancer cell line (A549) compounds **4a, 4b, 4d, 4f, 5d,** and **5g** were the most potent, with IC50 values ranging from 1.98 to 2.82 μM. On the HeLa cell line the compounds which showed potent activity were **4b, 4d, 5d,** and **5g** (IC50 = 1.99–2.92 μM). In case of the MCF-7 breast cancer cell line, the potent compounds were **4d, 5d,** and **5g** with IC50 activity of 2.12–2.52 μM. Lower activity was observed for the synthesized compounds on the Du-145 prostate cancer cell line, where the most potent candidates were compounds **5g** with IC50 activity in the range of 2.12 μM. Generally, the lung

> **HeLa (cervical cancer cell)**

4a 1.98 ± 0.12 3.83 ± 0.16 3.52 ± 0.06 3.86 ± 0.16 4b 2.81 ± 0.13 2.92 ± 0.08 2.32 ± 0.22 3.82 ± 0.12 4c 4.81 ± 0.12 6.32 ± 0.04 4.32 ± 0.06 3.73 ± 0.12 4d 2.82 ± 0.11 1.99 ± 0.22 2.36 ± 0.12 3.52 ± 0.11 4e 3.86 ± 0.08 4.38 ± 0.06 3.63 ± 0.12 6.52 ± 0.22 4f 2.72 ± 0.11 3.87 ± 0.08 4.12 ± 0.06 3.86 ± 0.22 4g 3.14 ± 0.14 3.98 ± 0.12 4.86 ± 0.11 4.57 ± 0.11 5a 8.48 ± 0.14 9.12 ± 0.08 7.82 ± 0.08 9.12 ± 0.06 5b 3.82 ± 0.08 4.13 ± 0.12 3.13 ± 0.11 3.52 ± 0.08 5c 4.13 ± 0.12 5.16 ± 0.08 6.12 ± 0.12 4.52 ± 0.11 5d 2.06 ± 0.12 2.12 ± 0.08 2.52 ± 0.16 5.12 ± 0.08 5e 2.52 ± 0.11 3.52 ± 0.11 4.48 ± 0.08 4.08 ± 0.11 5f 4.48 ± 0.08 4.98 ± 0.11 5.17 ± 0.22 5.18 ± 0.18 5g 2.73 ± 0.08 2.12 ± 0.12 2.12 ± 0.08 2.12 ± 0.04 5-FU 1.61 ± 0.12 1.72 ± 0.18 1.81 ± 0.10 1.89 ± 0.12

In vitro *anticancer screening of the synthesized compounds against four cell lines, data are expressed as IC50*

**MCF-7 (breast cancer cell)**

**Du-145 (prostate cancer cell)**

**110**

**Table 2.**

*(μM) SD (n = 3).*

(A549) and cervical (HeLa) cancer cell lines were the most sensitive to the synthesized compounds. With regard to broad spectrum anticancer activity, close examination of the data presented in **Table 2**, reveals that compounds **4b, 4d,** and **5g** were the most active, showing effectiveness toward the four cell lines. The structure activity relationship (SAR) can be explained on the basis of substitutions on both the aromatic rings less hindered substitution like methyl and ethyl on ortho and para position of rings increases the anticancer activity in all four cell lines, interestingly ortho triflouromethyl and indoline group decreases the anticancer activity and despite steric hindrance **4b**, **4d, 5d,** and **5g** shows promising activity because of electron donating tendency. Most of the compounds show promising anticancer activity with electron donating groups on the ring than electron withdrawing groups.

#### **2.3 General experimental procedure for the synthesis of N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide (5a-g)**

#### *2.3.1 Step-1: preparation of ethyl 3-(chlorosulfonyl)benzoate (2)*

To a stirred solution of ethyl benzoate (10 g, 67 mmol) in DCM (25 mL). RM was cooled to 0°C and chloro sulfonic acid (9 g, 73 mmol) was added drop wise and stirred for 1 h at same temperature followed by stirring at room temperature for 1 h. After completion of reaction, evaporate reaction mixture under reduced pressure and obtained gummy material is washed with excess of hexane and it is crystalized from 20% ethyl acetate: hexane mixture to obtain white solid as ethyl 3-(chlorosulfonyl)benzoate **(2)** which is used further for sulfonamide coupling reaction. Yield 54 g (81%).

#### *2.3.2 Step-2: preparation of ethyl 3-(N-(o-tolyl)sulfamoyl)benzoate (3a-g)*

To a stirred solution of ethyl 3-(chlorosulfonyl)benzoate **(2)** (3 g, 10.1 mmol) in DCM (5 ml) was added pyridine (5 ml) the mixture was stirred at room temperature for 10 min. RM was cooled to 0°C and 2-methyl aniline (1.6 g, 15.16 mmol) was added drop wise followed by stirring at room temperature for 3 h. The reaction was monitored by TLC and LCMS, after completion of reaction poured reaction mass on cold 2N aqueous HCl (10 ml) and stirred RM it for 30 min. Precipitation formed in RM. Filtered the obtained solid and wash it with excess of water and cold diethyl ether (10 ml) and cold pentane (10 ml) to obtain ethyl 3-(N-(o-tolyl)sulfamoyl) benzoate **2** as white solid. Yield 2.8 g (90%).

#### *2.3.3 Step-3: preparation of 3-(N-(o-tolyl)sulfamoyl)benzoic acid (4a-g)*

To a stirred solution of ethyl 3-(N-(o-tolyl)sulfamoyl)benzoate (**3a-g)** (2 g, 5.40 mmol) in THF (10 ml) added water (2 ml), and lithium hydroxide (0.377 g, 18.2 mmol) and stirred reaction mixture for 4 h. Progress reaction was monitored by TLC and LCMS. After the completion of reaction evaporate reaction mixture under reduced pressure to obtain gummy material. Added 10 ml of water in it and extracted it with diethyl ether (10 ml). Collected aqueous layer and adjust its pH to 4 by using 6N aqueous HCl. Precipitation occurs stirred it for 30 min. Filtered the obtained solid and wash it with excess of water, cold diethyl ether (10 ml) and cold pentane (10 ml) to obtain desired 3-(N-(o-tolyl)sulfamoyl)benzoic acid **4a** as white solids. Yield 1.6 g (90%).

#### *2.3.4 Step-4: N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide (5a-g)*

The compound 3-(N-(o-tolyl)sulfamoyl)benzoic acid **4a-g** (0.2 g, 0.65 mmol) was treated with EDCI (0.188 g, 0.98 mmol), DIPEA (0.34 ml, 1.96 mmol) in DCM (10 ml). Then added 2,4-dimentyl aniline (0.238 g, 1.96 mmol) and stirred RM at room temperature for 4 h. The reaction was monitored by TLC. Added 10 ml of cold water and stirred for 10 min, then extracted it with 10 ml of DCM. Collected organic layer wash it with 1N aqueous HCl and washed with brine (10 ml). To evaporate the organic layer to obtained the compound with 90% purity (**5a-g).** Purification done by washing with 5:95% of DCM: hexane. Obtained solid washed with cold diethyl ether (20 ml) and cold pentane (20 ml) to obtain compounds (**5a-g**). N-(2,4-dimethylphenyl)-3-(N-(o-tolyl)sulfamoyl)benzamide (**5a):** (0.240 g, 90%) as white solid, LC-MS *m/z* (%): 395 (M + H). 1 H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.70 (s, 1H), 8.26 (s, 1H), 8.22 (d, *J* = 7.6 Hz, 1H), 7.81 (d, *J* = 8 Hz, 1H), 7.7 (d, *J* = 8 Hz, 1H), 7.18–7.13 (m, 2H), 7.1–7.08 (m, 3H), 7.01 (d, *J* = 8.4 Hz, 1H), 6.95–6.92 (m, 1H), 2.28 (s, 3H), 2.15 (s, 3H), 2.02 (s, 3H). HPLC-98.25% RT-5.68 min. 13C NMR (CDCl3, 100 MHZ): 17.65, 17.79, 20.54, 126.09, 126.38, 126.40, 126.43, 126.58, 129.23, 129.42, 130.82, 130.89, 131.38, 133.42, 133.62, 134.27, 134.65, 135.40, 135.41, 135.45, 141.09, 163.93.

#### **3. Conclusion**

An effective method was developed which provided an easy access to a new series N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide (**5a-g**) analogs. The mild reaction conditions, good to excellent yields, ease of workup and easily available substrates make the reactions attractive for the preparation of compounds. The compounds (**4b, 4d, 5d,** and **5g**) show potent anticancer activity in all the four cell lines tested. The compounds are easy, simple and reproducible to synthesize in normal conditions and no additional conditions or expensive chemicals are required for the reaction. The cell-lines with maximum IC50 values are the important in the study.

#### **Acknowledgements**

The authors are thankful to the Head, Department of Chemistry, Deogiri college, Aurangabad for the laboratory facility.

**113**

**Author details**

Dattatraya Navnath Pansare\* and Rohini Narayan Shelke

provided the original work is properly cited.

Department of Chemistry, Deogiri College, Aurangabad, MS, 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,

\*Address all correspondence to: dattatraya.pansare7@gmail.com

*Synthesis and Anticancer Evaluation of Benzenesulfonamide Derivatives*

*DOI: http://dx.doi.org/10.5772/intechopen.88139*

*Synthesis and Anticancer Evaluation of Benzenesulfonamide Derivatives DOI: http://dx.doi.org/10.5772/intechopen.88139*

*Heterocycles - Synthesis and Biological Activities*

as white solid, LC-MS *m/z* (%): 395 (M + H). 1

135.40, 135.41, 135.45, 141.09, 163.93.

**3. Conclusion**

important in the study.

**Acknowledgements**

Aurangabad for the laboratory facility.

*(5a-g)*

*2.3.4 Step-4: N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide* 

The compound 3-(N-(o-tolyl)sulfamoyl)benzoic acid **4a-g** (0.2 g, 0.65 mmol) was treated with EDCI (0.188 g, 0.98 mmol), DIPEA (0.34 ml, 1.96 mmol) in DCM (10 ml). Then added 2,4-dimentyl aniline (0.238 g, 1.96 mmol) and stirred RM at room temperature for 4 h. The reaction was monitored by TLC. Added 10 ml of cold water and stirred for 10 min, then extracted it with 10 ml of DCM. Collected organic layer wash it with 1N aqueous HCl and washed with brine (10 ml). To evaporate the organic layer to obtained the compound with 90% purity (**5a-g).** Purification done by washing with 5:95% of DCM: hexane. Obtained solid washed with cold diethyl ether (20 ml) and cold pentane (20 ml) to obtain compounds (**5a-g**). N-(2,4-dimethylphenyl)-3-(N-(o-tolyl)sulfamoyl)benzamide (**5a):** (0.240 g, 90%)

10.05 (s, 1H), 9.70 (s, 1H), 8.26 (s, 1H), 8.22 (d, *J* = 7.6 Hz, 1H), 7.81 (d, *J* = 8 Hz, 1H), 7.7 (d, *J* = 8 Hz, 1H), 7.18–7.13 (m, 2H), 7.1–7.08 (m, 3H), 7.01 (d, *J* = 8.4 Hz, 1H), 6.95–6.92 (m, 1H), 2.28 (s, 3H), 2.15 (s, 3H), 2.02 (s, 3H). HPLC-98.25% RT-5.68 min. 13C NMR (CDCl3, 100 MHZ): 17.65, 17.79, 20.54, 126.09, 126.38, 126.40, 126.43, 126.58, 129.23, 129.42, 130.82, 130.89, 131.38, 133.42, 133.62, 134.27, 134.65,

An effective method was developed which provided an easy access to a new series N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide (**5a-g**) analogs. The mild reaction conditions, good to excellent yields, ease of workup and easily available substrates make the reactions attractive for the preparation of compounds. The compounds (**4b, 4d, 5d,** and **5g**) show potent anticancer activity in all the four cell lines tested. The compounds are easy, simple and reproducible to synthesize in normal conditions and no additional conditions or expensive chemicals are required for the reaction. The cell-lines with maximum IC50 values are the

The authors are thankful to the Head, Department of Chemistry, Deogiri college,

H NMR (400 MHz, DMSO-d6) δ

**112**

#### **Author details**

Dattatraya Navnath Pansare\* and Rohini Narayan Shelke Department of Chemistry, Deogiri College, Aurangabad, MS, India

\*Address all correspondence to: dattatraya.pansare7@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-dihydrothiazol-2-yl)amino) substituted acid using microwave irradiation and conventional method.

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4666170524142722

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[27] Pawar CD, Chavan SL, Pawar UD, Pansare DN, Deshmukh SV, Shinde DB. Synthesis, anti-proliferative activity, SAR and kinase inhibition studies of thiazol-2-yl-substituted sulfonamide derivatives. Journal of the Chinese Chemical Society. 2018. DOI: 10.1002/

acid. Journal of Saudi Chemical Society. 2017;**21**:434. DOI: 10.1016/j.

jscs.2015.10.005

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Kumar KV, Zhou CH. Synthesis of novel sulfonamide azoles via C-N cleavage of sulfonamides by azole ring and relational antimicrobial study. New Journal of Chemistry. 2015;**39**:5776.

*DOI: http://dx.doi.org/10.5772/intechopen.88139*

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[19] Sławinski J, Szafranski K, Vullo D, Supuran CT. Carbonic anhydrase inhibitors. Synthesis of heterocyclic 4-substituted pyridine-3-sulfonamide derivatives and their inhibition of the human cytosolic isozymes I and II and transmembrane tumor-associated isozymes IX and XII. European Journal of Medicinal Chemistry. 2013;**69**:701. DOI: 10.1016/j.

ejmech.2013.09.027

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Mandi P, Nantasenamat C,

[21] Pingaew R, Prachayasittikul V,

Prachayasittikul S, Ruchirawat S, et al. Synthesis and molecular docking of 1,2,3-triazole-based sulfonamides as aromatase inhibitors. Bioorganic & Medicinal Chemistry. 2015;**23**:3472. DOI: 10.1016/j.bmc.2015.04.036

C5RA16581D

[20] Mirjafary Z, Ahmadi L, Moradi M, Saeidian H. A copper(II)-thioamide combination as a robust heterogeneous catalytic system for green synthesis of 1,4-disubstituted-1,2,3-triazoles under click conditions. RSC Advances.

[18] Kwon Y, Song J, Lee H, Kim EY, Lee K, Lee SK, et al. Design, synthesis, and biological activity of sulfonamide analogues of antofine and cryptopleurine as potent and orally active antitumor agents. Journal of Medicinal Chemistry. 2015;**58**:7749. DOI: 10.1021/acs.jmedchem.5b00764

[16] Zia-ur-Rehman M,

2006;**54**:1175

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[16] Zia-ur-Rehman M, Choudary JA, Ahmad S, Siddiqui HL. Synthesis of potential biologically active 1,2-benzothiazin-3-ylquinazolin-4(3H)-ones. Chemical & Pharmaceutical Bulletin. 2006;**54**:1175

[17] Hendricks RT, Spencer SR, Blake JF. 3-Hydroxyisoquinolines as inhibitors of HCV NS5b RNA-dependent RNA polymerase. Bioorganic & Medicinal Chemistry Letters. 2009;**19**:410. DOI: 10.1016/j.bmcl.2008.11.060

[18] Kwon Y, Song J, Lee H, Kim EY, Lee K, Lee SK, et al. Design, synthesis, and biological activity of sulfonamide analogues of antofine and cryptopleurine as potent and orally active antitumor agents. Journal of Medicinal Chemistry. 2015;**58**:7749. DOI: 10.1021/acs.jmedchem.5b00764

[19] Sławinski J, Szafranski K, Vullo D, Supuran CT. Carbonic anhydrase inhibitors. Synthesis of heterocyclic 4-substituted pyridine-3-sulfonamide derivatives and their inhibition of the human cytosolic isozymes I and II and transmembrane tumor-associated isozymes IX and XII. European Journal of Medicinal Chemistry. 2013;**69**:701. DOI: 10.1016/j. ejmech.2013.09.027

[20] Mirjafary Z, Ahmadi L, Moradi M, Saeidian H. A copper(II)-thioamide combination as a robust heterogeneous catalytic system for green synthesis of 1,4-disubstituted-1,2,3-triazoles under click conditions. RSC Advances. 2015;**5**:78038. DOI: 10.1039/ C5RA16581D

[21] Pingaew R, Prachayasittikul V, Mandi P, Nantasenamat C, Prachayasittikul S, Ruchirawat S, et al. Synthesis and molecular docking of 1,2,3-triazole-based sulfonamides as aromatase inhibitors. Bioorganic & Medicinal Chemistry. 2015;**23**:3472. DOI: 10.1016/j.bmc.2015.04.036

[22] Wang XL, Wan K, Zhou CH. Synthesis of novel sulfanilamidederived 1,2,3-triazoles and their evaluation for antibacterial and antifungal activities. European Journal of Medicinal Chemistry. 2010;**45**:4631. DOI: 10.1016/j.ejmech.2010.07.031

[23] Zhang Z, Jeyakkumar P, Kumar KV, Zhou CH. Synthesis of novel sulfonamide azoles via C-N cleavage of sulfonamides by azole ring and relational antimicrobial study. New Journal of Chemistry. 2015;**39**:5776. DOI: 10.1039/C4NJ01932F

[24] Pansare DN, Shelke RN, Pawar CD. A facile synthesis of (Z)- 2-((5-(4-chlorobenzylidene)-4-oxo-4, 5-dihydrothiazol-2-yl)amino) substituted acid using microwave irradiation and conventional method. Letters in Organic Chemistry. 2017;**14**(7):517. DOI: 10.2174/157017861 4666170524142722

[25] Pansare DN, Shelke RN, Shinde DB. A facial synthesis and anticancer activity of (Z)-2-((5- (4-nitrobenzylidene)-4-oxo-4,5 dihydrothiazol-2-yl)amino) substituted acid. Journal of Heterocyclic Chemistry. 2017;**54**(6):3077. DOI: 10.1002/jhet.2919

[26] Pansare DN, Shinde DB. A facile synthesis of novel series (Z)-2-((4 oxo-5-(thiophen-2-yl methylene)-4,5 dihydro thiazol-2-yl)amino) substituted acid. Journal of Saudi Chemical Society. 2017;**21**:434. DOI: 10.1016/j. jscs.2015.10.005

[27] Pawar CD, Chavan SL, Pawar UD, Pansare DN, Deshmukh SV, Shinde DB. Synthesis, anti-proliferative activity, SAR and kinase inhibition studies of thiazol-2-yl-substituted sulfonamide derivatives. Journal of the Chinese Chemical Society. 2018. DOI: 10.1002/ jccs.201800312

[28] Pawar CD, Pansare DN, Shinde DB. (Substituted)-benzo[b]

**114**

*Heterocycles - Synthesis and Biological Activities*

[1] Walsh CT, Wencewicz TA. Prospects for new antibiotics: A molecule-centered perspective. The Journal of Antibiotics. 2013;**67**:7. DOI: 10.1038/ja.2013.49

[9] Scozzafava A, Briganti F, Ilies MA, Supuran CT. Carbonic anhydrase inhibitors: Synthesis of membraneimpermeant low molecular weight sulfonamides possessing in vivo selectivity for the membrane-bound versus cytosolic isozymes. Journal of Medicinal Chemistry. 2000;**43**:292.

[10] Scozzafava A, Supuran CT. Protease

DOI: 10.1021/jm990479+

S0968-0896(99)00316-8

[11] Levitt G. Agricultural

science.287.5460.1960

DOI: 10.1021/jm010178b

[14] Brooke EW, Davies SG,

S0960-894X(03)00484-0

[15] Bihovsky R, Tao M,

bmcl.2003.11.037

as potent calpain I inhibitors. Bioorganic & Medicinal Chemistry Letters. 2004;**14**:1035. DOI: 10.1016/j.

[12] Drews J. Drug discovery: A historical perspective. Science. 2000;**287**:1960. DOI: 10.1126/

[13] Wells GJ, Tao M, Josef KA, Bihovsky R. 1,2-Benzothiazine

1,1-dioxide P(2)-P(3) peptide mimetic aldehyde calpain I inhibitors. Journal of Medicinal Chemistry. 2001;**44**:3488.

Mulvaney WA. Synthesis and in vitro evaluation of novel small molecule inhibitors of bacterial arylamine N-acetyltransferases (NATs). Bioorganic & Medicinal Chemistry Letters. 2003;**13**:2527. DOI: 10.1016/

Mallamo JP, Wells GJ. 1,2-Benzothiazine 1,1-dioxide alpha-ketoamide analogues

113; 1983

sulfonamides. U. S. Patent No. 4, 383,

inhibitors. Part 8: Synthesis of potent *Clostridium histolyticum* collagenase inhibitors incorporating sulfonylated L-alanine hydroxamate moieties. Bioorganic & Medicinal Chemistry. 2000;**8**:637. DOI: 10.1016/

[2] Alvarez M, Salas M, Joule JA. Marine,

containing indole units. Heterocycles. 1991;**32**(7):1391. DOI: 10.3987/

[4] Mantle PG. The role of tryptophan as a biosynthetic precursor of indolediterpenoid fungal metabolites: Continuing a debate. Phytochemistry.

2009;**70**(1):7. DOI: 10.1016/j. phytochem.2008.11.004

[5] Jones RSG. Tryptamine: A

neuromodulator or neurotransmitter in mammalian brain. Progress in Neurobiology. 1982;**19**(1-2):117. DOI: 10.1016/0301-0082(82)90023-5

[6] Folkes LK, Wardman P. Oxidative activation of indole-3-acetic acids to cytotoxic species—A potential new role for plant auxins in cancer therapy. Biochemical Pharmacology;**61**(2):129. DOI: 10.1016/S0006-2952(00)00498-6

[7] Abdel-Rahman AH, Keshk EM, Hanna MA, El-Bady SM. Bioorganic & Medicinal Chemistry. 2004;**12**(9):2483.

DOI: 10.1016/j.bmc.2003.10.063

[8] Scozzafava A, Owa T, Mastrolorenzo A, Supuran CT. Anticancer and antiviral sulfonamides. Current Medicinal Chemistry. 2003;**10**:925. DOI: 10.2174/0929867033457647

nitrogen-containing heterocyclic natural products—Structures and syntheses of compounds

[3] Ruiz-Sanchis P, Savina SA, Albericio F, Alvarez M. Structure, bioactivity and synthesis of natural products with hexahydropyrrolo[2,3-b] indole. Chemistry—A European Journal. 2011;**17**(5):1388. DOI: 10.1002/

**References**

rev-91-429

chem.201001451

thiophene-4-carboxamide synthesis and anti-proliferative activity study. Letters in Drug Design & Discovery. 2018. DOI: 10.2174/1570180815666181004114125

[29] Pawar CD, Pansare DN, Shinde DB. Synthesis of new 3-(substituted phenyl)-N-(2-hydroxy-2-(substituted phenyl)ethyl)- N-methylthiophene-2-sulfonamide derivatives as antiproliferative agents. European Journal of Chemistry. 2018;**9**(1):13. DOI: 10.5155/ eurjchem.9.1.13-21.1669

[30] Pawar CD, Pansare DN, Shinde DB. Synthesis and antiproliferative activity of 3-(substituted)-4,5,6,7-tetrahydro-6-(substituted)-1H-pyrazolo[3,4-c] pyridine derivatives. European Journal of Chemistry. 2017;**8**(4):400. DOI: 10.5155/eurjchem.8.4.400-409.1645

[31] Skehan P, Storeng R, Scudiero D, Monks A, McMohan J, Vistica D, et al. New colorimetric cytotoxicity assay for anticancer-drug screening. Journal of the National Cancer Institute. 1990;**82**:1107

**117**

nal chemists.

**Chapter 9**

*Avula Srinivas*

**Abstract**

**1. Introduction**

Synthesis and Biological

Thiazolo Pyrazoles

Evaluation of Novel Phosphonyl

A series of novel dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-8-phenyl-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate **11a–g** were synthesized by the reaction of chalcone derivatives of (E)-5-benzylidene-2-((2S,3S)-3-((1- (4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)- 3-phenylthiazolidin-4-one **10a–g** with Bestmann-Ohira reagent. The chemical structures of newly synthesized compounds were elucidated by IR, NMR, MS, and elemental analysis. The compounds **11a–g** were evaluated for their nematicidal activity against *Dietylenchus myceliophagus* and *Caenorhabditis elegans*, and com-

pounds **11b**, **11c**, **11g**, and **11f** showed appreciable nematicidal activity.

**Keywords:** phosponylpyrazoles, Bestmann-Ohira reagent, click reaction,

1,2,3-Triazoles are one of the most important classes of heterocyclic organic compounds, which are reported to present in a plethora of biological activities for diverse therapeutic areas [1–12]. The 1,2,3-triazole motif is associated with diverse pharmacological activities such as antibacterial, antifungal, hypoglycemic, antihypertensive and analgesic properties [13–15]. Polysubstituted five-membered aza heterocyclic's rank the most potent glycosidase inhibitors [16–19]. Further, this nucleus in combination with or in linking with various other classes of compounds such as amino acids, steroids, aromatic compounds, carbohydrates etc. became prominent in having various pharmacological properties [20]. 1,2,3-Triazole modified carbohydrates have became easily available after the discovery of the Cu(I) catalyzed azide-alkynes 1,3-dipolar cycloaddition reaction [21–25] and quickly became a prominent class of non-natural sugars. The chemistry and biology of triazole modified sugars is dominated by triazole glycosides [26]. Therefore, the synthesis and investigation of biological activity of 1,2,3-triazole glycosides is an important objective, which also received the considerable attention by the medici-

Thiazoles are familiar group of heterocyclic compounds possessing a wide variety of biological activities and their utility as medicine is very much established [27]. Thiazole nucleus is also an integral part of all the available penicillins

Knoevenagel condensation, cyclisation, nematicidal activity

#### **Chapter 9**

*Heterocycles - Synthesis and Biological Activities*

thiophene-4-carboxamide synthesis and anti-proliferative activity study. Letters in Drug Design & Discovery. 2018. DOI: 10.2174/1570180815666181004114125

3-(substituted phenyl)-N-(2-hydroxy-

[30] Pawar CD, Pansare DN, Shinde DB. Synthesis and antiproliferative activity of 3-(substituted)-4,5,6,7-tetrahydro-6-(substituted)-1H-pyrazolo[3,4-c] pyridine derivatives. European Journal of Chemistry. 2017;**8**(4):400. DOI: 10.5155/eurjchem.8.4.400-409.1645

[31] Skehan P, Storeng R, Scudiero D, Monks A, McMohan J, Vistica D, et al. New colorimetric cytotoxicity assay for anticancer-drug screening. Journal of the National Cancer Institute.

1990;**82**:1107

[29] Pawar CD, Pansare DN, Shinde DB. Synthesis of new

2-(substituted phenyl)ethyl)- N-methylthiophene-2-sulfonamide derivatives as antiproliferative agents. European Journal of Chemistry. 2018;**9**(1):13. DOI: 10.5155/ eurjchem.9.1.13-21.1669

**116**

## Synthesis and Biological Evaluation of Novel Phosphonyl Thiazolo Pyrazoles

*Avula Srinivas*

#### **Abstract**

A series of novel dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-8-phenyl-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate **11a–g** were synthesized by the reaction of chalcone derivatives of (E)-5-benzylidene-2-((2S,3S)-3-((1- (4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)- 3-phenylthiazolidin-4-one **10a–g** with Bestmann-Ohira reagent. The chemical structures of newly synthesized compounds were elucidated by IR, NMR, MS, and elemental analysis. The compounds **11a–g** were evaluated for their nematicidal activity against *Dietylenchus myceliophagus* and *Caenorhabditis elegans*, and compounds **11b**, **11c**, **11g**, and **11f** showed appreciable nematicidal activity.

**Keywords:** phosponylpyrazoles, Bestmann-Ohira reagent, click reaction, Knoevenagel condensation, cyclisation, nematicidal activity

#### **1. Introduction**

1,2,3-Triazoles are one of the most important classes of heterocyclic organic compounds, which are reported to present in a plethora of biological activities for diverse therapeutic areas [1–12]. The 1,2,3-triazole motif is associated with diverse pharmacological activities such as antibacterial, antifungal, hypoglycemic, antihypertensive and analgesic properties [13–15]. Polysubstituted five-membered aza heterocyclic's rank the most potent glycosidase inhibitors [16–19]. Further, this nucleus in combination with or in linking with various other classes of compounds such as amino acids, steroids, aromatic compounds, carbohydrates etc. became prominent in having various pharmacological properties [20]. 1,2,3-Triazole modified carbohydrates have became easily available after the discovery of the Cu(I) catalyzed azide-alkynes 1,3-dipolar cycloaddition reaction [21–25] and quickly became a prominent class of non-natural sugars. The chemistry and biology of triazole modified sugars is dominated by triazole glycosides [26]. Therefore, the synthesis and investigation of biological activity of 1,2,3-triazole glycosides is an important objective, which also received the considerable attention by the medicinal chemists.

Thiazoles are familiar group of heterocyclic compounds possessing a wide variety of biological activities and their utility as medicine is very much established [27]. Thiazole nucleus is also an integral part of all the available penicillins which have revolutionized the therapy of bacterial diseases [28]. The chemistry of thiazolidinone ring system is one of considerable interest as it is the core structure in various synthetic pharmaceuticals displaying a broad spectrum of biological activities [29]. The thiazolidinone nucleus also appears frequently in the structure of various natural products notably thiamine, compounds possessing cardiac and glycemic benefits such as troglitazone [30] and many metabolic products of fungi and primitive marine animals, including 2-(aminoallyl)-thiazole-4-carboxylic acids [31]. Numerous thiazolidinone derivatives have shown significant bio activities such as antidiarrhoeal [32], anticonvulsant [33], antimicrobial [34], antidiabetic [35], antihistaminic [36], anticancer [37], anti HIV [38], Ca2+ channel blocker [39], PAF antagonist [40], cardioprotective [41], antiischemic [42], COX inhibitory [43], antiplatelet activating factor [44], non-peptide thrombin receptor antagonist [45], tumor necrosis factor-*α*-antagonist [46] and nematicidal activities. Organophosphorus compounds continue to attract much attention because of their various potent biological activities [47, 48] in particular, phosphonates are important synthetic derivatives which can have often act as phosphate and carboxylic acid mimics, and interfere with enzymatic processes. Much of this activity has been attributed to the relatively inert nature of the C▬P bond [47, 48], which is not easily hydrolyzed as compared to the P▬O bond found in phosphates. The synthesis and biological activities of important natural and nonnatural phosphonate derivatives, including phosphonated aza heterocyclics and nucleotides, have been reviewed [49–51]. In view of the importance of heterocyclics bearing a phosphonate group, new synthetic methods that would allow straightforward access to these versatile building blocks are needed [47, 48, 52]. Among the various bioactive heterocyclics the pyrazole moiety remains of great interest because of its wide applications in the pharmaceutical and agrochemical industry [53, 54]. In addition, pyrazoles also play a central role in coordination chemistry [55].

Nematodes are tiny worms, some of them are plant parasites, and can play an important role in the predisposition of the host plant to the invasion by secondary pathogens [56]. Plants attacked by nematodes show retarded growth and development, as well as loss in the quality and quantity of the harvest. The nematicide use is slated for reduction due to environmental problems, and human and animal health concern. For example, effective nematicides such as dibromochloropropane (DBCD) and ethylene dibromide (EDB) have been withdrawn from the market due to their deleterious effects on human and the environment. Methyl bromide, the most effective and widely used fumigant for soil borne pests including nematodes, has already been banned.

The use of nonfumigant nematicides, based on organophosphates and carbamates, is expected to increase the withdrawal of methyl bromide, which will bring about new environmental concerns. In fact, the highly toxic aldicarb used to control insects and nematodes has been detected in ground water [57]. Therefore alternative nematode control methods or less toxic nematicides need to be developed [58]. One way of searching for such nematicidal compounds is to screen naturally occurring compounds in plants. Several such compounds, e.g., alkaloids, phenols, sesquiterpenes, diterpenes, polyacetylenes, and thienyl derivatives have nematicidal activity [59]. For example, *α*-terthienyl is a highly effective nematicidal compound [60]. Other compounds with nematicidal activity have been isolated from plants, mainly from the family *Asteraceae* [59]. However, compounds of plant origin and their analogs have not been developed into commercial nematicides; hence there is a need to develop commercial synthesis.

Following the successful introduction of nematicidal agents, inspired by the biological profile of triazoles, thiazoles, Phosponylpyrazoles. In continuation of

**119**

**Figure 1.**

*(g) 2-OH-C6H5.*

*Synthesis and Biological Evaluation of Novel Phosphonyl Thiazolo Pyrazoles*

our work on biological active molecules [61–69] it was thought to interest to accommodate all those moieties in single molecular frame work. In this article we wish to report the synthesis of a new class of hybrid heterocyclic's **11a–g** in good yields and

The key intermediate, **8** required for the synthesis of title compound was prepared according to the procedure outlined in **Figure 1**. Diacetyl-D-glucal **(2)** prepared from 3,4,6-tri-O-acetyl D-glucal by treating with triethyl silane and boron trifluoride diethyl etherate, de acylation of **2**, with NaOMe in methanol at 0°C for 1 hour gave **3** (77%), which on subsequent treatment with TBDMSCl in dichloromethane in presence of NEt3 for 12 hours afforded TBS ether **4** (80%), on treatment with propargyl bromide in toluene in presence of tetra butyl ammonium hydrogen sulfate produced di ether **5**. After deprotection of TBS ether the propargyl ether converted into triazole **7** (82%) by using 1,3-dipolar cycloaddition with *p*-chloro phenyl azide was carried out at ambient temperature in the presence of CuSO4 and sodium ascorbate in a mixture of 1:1 CH2Cl2-H2O. Oxidation of **7** with IBX in

*R= (a) C6H5; (b) 4-Cl-C6H5; (c) 4-NO2-C6H5; (d) 2-CH3-C6H5; (e) 4-CH3-C6H5; (f) 3-OH-C6H5;* 

*DOI: http://dx.doi.org/10.5772/intechopen.86977*

their evaluated nematicidal activity.

**2. Result and discussion**

*Synthesis and Biological Evaluation of Novel Phosphonyl Thiazolo Pyrazoles DOI: http://dx.doi.org/10.5772/intechopen.86977*

our work on biological active molecules [61–69] it was thought to interest to accommodate all those moieties in single molecular frame work. In this article we wish to report the synthesis of a new class of hybrid heterocyclic's **11a–g** in good yields and their evaluated nematicidal activity.

#### **2. Result and discussion**

*Heterocycles - Synthesis and Biological Activities*

which have revolutionized the therapy of bacterial diseases [28]. The chemistry of thiazolidinone ring system is one of considerable interest as it is the core structure in various synthetic pharmaceuticals displaying a broad spectrum of biological activities [29]. The thiazolidinone nucleus also appears frequently in the structure of various natural products notably thiamine, compounds possessing cardiac and glycemic benefits such as troglitazone [30] and many metabolic products of fungi and primitive marine animals, including 2-(aminoallyl)-thiazole-4-carboxylic acids [31]. Numerous thiazolidinone derivatives have shown significant bio activities such as antidiarrhoeal [32], anticonvulsant [33], antimicrobial [34], antidiabetic [35], antihistaminic [36], anticancer [37], anti HIV [38], Ca2+ channel blocker [39], PAF antagonist [40], cardioprotective [41], antiischemic [42], COX inhibitory [43], antiplatelet activating factor [44], non-peptide thrombin receptor antagonist [45], tumor necrosis factor-*α*-antagonist [46] and nematicidal activities. Organophosphorus compounds continue to attract much attention because of their various potent biological activities [47, 48] in particular, phosphonates are important synthetic derivatives which can have often act as phosphate and carboxylic acid mimics, and interfere with enzymatic processes. Much of this activity has been attributed to the relatively inert nature of the C▬P bond [47, 48], which is not easily hydrolyzed as compared to the P▬O bond found in phosphates. The synthesis and biological activities of important natural and nonnatural phosphonate derivatives, including phosphonated aza heterocyclics and nucleotides, have been reviewed [49–51]. In view of the importance of heterocyclics bearing a phosphonate group, new synthetic methods that would allow straightforward access to these versatile building blocks are needed [47, 48, 52]. Among the various bioactive heterocyclics the pyrazole moiety remains of great interest because of its wide applications in the pharmaceutical and agrochemical industry [53, 54]. In addition,

pyrazoles also play a central role in coordination chemistry [55].

Nematodes are tiny worms, some of them are plant parasites, and can play an important role in the predisposition of the host plant to the invasion by secondary pathogens [56]. Plants attacked by nematodes show retarded growth and development, as well as loss in the quality and quantity of the harvest. The nematicide use is slated for reduction due to environmental problems, and human and animal health concern. For example, effective nematicides such as dibromochloropropane (DBCD) and ethylene dibromide (EDB) have been withdrawn from the market due to their deleterious effects on human and the environment. Methyl bromide, the most effective and widely used fumigant for soil borne pests including nematodes,

The use of nonfumigant nematicides, based on organophosphates and carbamates, is expected to increase the withdrawal of methyl bromide, which will bring about new environmental concerns. In fact, the highly toxic aldicarb used to control insects and nematodes has been detected in ground water [57]. Therefore alternative nematode control methods or less toxic nematicides need to be developed [58]. One way of searching for such nematicidal compounds is to screen naturally occurring compounds in plants. Several such compounds, e.g., alkaloids, phenols, sesquiterpenes, diterpenes, polyacetylenes, and thienyl derivatives have nematicidal activity [59]. For example, *α*-terthienyl is a highly effective nematicidal compound [60]. Other compounds with nematicidal activity have been isolated from plants, mainly from the family *Asteraceae* [59]. However, compounds of plant origin and their analogs have not been developed into commercial nematicides; hence there is a

Following the successful introduction of nematicidal agents, inspired by the biological profile of triazoles, thiazoles, Phosponylpyrazoles. In continuation of

**118**

has already been banned.

need to develop commercial synthesis.

The key intermediate, **8** required for the synthesis of title compound was prepared according to the procedure outlined in **Figure 1**. Diacetyl-D-glucal **(2)** prepared from 3,4,6-tri-O-acetyl D-glucal by treating with triethyl silane and boron trifluoride diethyl etherate, de acylation of **2**, with NaOMe in methanol at 0°C for 1 hour gave **3** (77%), which on subsequent treatment with TBDMSCl in dichloromethane in presence of NEt3 for 12 hours afforded TBS ether **4** (80%), on treatment with propargyl bromide in toluene in presence of tetra butyl ammonium hydrogen sulfate produced di ether **5**. After deprotection of TBS ether the propargyl ether converted into triazole **7** (82%) by using 1,3-dipolar cycloaddition with *p*-chloro phenyl azide was carried out at ambient temperature in the presence of CuSO4 and sodium ascorbate in a mixture of 1:1 CH2Cl2-H2O. Oxidation of **7** with IBX in

**Figure 1.** *R= (a) C6H5; (b) 4-Cl-C6H5; (c) 4-NO2-C6H5; (d) 2-CH3-C6H5; (e) 4-CH3-C6H5; (f) 3-OH-C6H5; (g) 2-OH-C6H5.*

acetonitrile afforded compound **8**. Subsequently one pot synthesis of triazole linked thiazolidinone glycosides was carried out by the condensation reaction between **8**, primary aromatic amine and a thio glycolic acid in presence of ZnCl2 under microwave irradiation (**Figure 1**). The reaction is completed in only 5–10 minutes and the compounds, isolated by conventional work-up, (**9a–g**) are obtained in satisfactory yields, Compound **9a–g** was then reacted with *p*-fluoro benzaldehyde in presence of anhydrous NaOAc in glacial AcOH at reflux temperature gave chalcone derivatives of triazole linked thiazolidinone glycosides **10a–g**, on cyclocondensation under conventional and microwave irradiation with Bestmann-Ohira reagent in presence of anhydrous KOH gave compounds **11(a–g)**. The structures of synthesized compounds were confirmed by IR, NMR, MS and elemental analysis. Further the compounds were subject to nematicidal activity testing.

#### **3. Nematicidal activity**

The compounds synthesized **10a-g** in this study were also screened for their nematicidal activity against *Dietylenchus myceliophagus* and *Caenorhabditis elegans* by aqueous *in vitro* screening technique [70] at various concentrations. The nematicidal activity of each test compound was compared with the standard drug *Levamisole*. The results have been expressed in terms of LD50 i.e., median lethal dose at which 50% nematodes became immobile (dead). The screened data reveal that, compounds **11b**, **11c**, **11f** and **11g** are the most effective against *Dietylenchus myceliophagus* and *Caenorhabditis elegans* the other test compounds showed moderate activity. The LD50 values of the test compounds screened are presented in **Table 1**.


**Table 1.**

*Nematicidal activity of 11(a–g).*

#### **4. Experimental**

Commercial grade reagents were used as supplied. Solvents except analytical reagent grade were dried and purified according to literature when necessary. Di-methyl 2-oxopropyl phosphonate was purchased from Aldrich for the synthesis o Bestmann-Ohira reagent. Reaction progress and purity of the compounds were checked by thin-layer chromatography (TLC) on pre-coated silica gel F254 plates from Merck and compounds visualized either by exposure to UV light or dipping in 1% aqueous potassium permanganate solution. Silica gel chromatographic columns

**121**

*Synthesis and Biological Evaluation of Novel Phosphonyl Thiazolo Pyrazoles*

(60–120 mesh) were used for separations. Optical rotations were measured on a Perkin-Elmer 141 polarimeter by using a 2 ml cell with a path length of 1 dm with CHCl3 or CDCl3 as solvent. All melting points are uncorrected and measured using Fisher-Johns apparatus. IR spectra were recorded as KBr disks on a Perkin-Elmer FTIR spectrometer. Micro wave reactions are carried out in mini lab microwave

Chemical shifts are reported as δ ppm against TMS as internal reference and coupling constants (*J*) are reported in Hz units. Mass spectra were recorded on a VG micro mass 7070H spectrometer. Elemental analysis (C, H, N) determined by a Perkin-Elmer 240 CHN elemental analyzer, were within ±0.4% of theoretical. *((2R,3S)-3-acetoxy-3,6-dihydro-2H-pyran-2-yl)methyl acetate* **(2)**: Tri-*O*acetyl-D-glucal (**1**) (3.0 g, 11.02 mmol) was dissolved in anhydrous dichloromethane (5 ml). The solution was cooled to 0°C, triethyl silane (1.53 g, 13.22 mmol) was added and the mixture was stirred for 5 minutes. Next boron tri fluoride diethyl etherate (690 μl of a 40 w% solution in diethyl ether, 11.02 mmol) was added drop wise and the reaction mixture was stirred for 90 minutes. The mixture was poured into a saturated solution of NaHCO3. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure. Column chromatography on silica gel (PE/EtOAc, 3:1) yielded the title compound (2.24 g, 10.42 mmol,

CDCl3): δ 5.87-5.84 (m, 2H, =CH),4.95 (t,1H, OCH),4.03-3.99 (m, 1H, CH),4.12- 4.09 (m,4H, OCH2), 2.20 (s, 6H, COCH3);13C NMR (75 MHz, CDCl3): δ170.2, 127.2,

**(2R,3S)-2-((tert-butyldimethylsilyloxy)methyl)-3,6-dihydro-2H-pyran-3-ol (4)**: Diacetate **2** (17.22 mmol) was treated by a catalytic amount of sodium methoxide in methanol (100 ml) at room temperature. After evaporation of the solvent, the free hydroxyl unsaturated glycoside was obtained in quantitative yield and used without further purification. This diol was treated with 2.50 equiv. of TBD MSCl (3.14 g, 21.14 mmol), 2.6 equiv. of NEt3 (3.2 ml, 22.4 mmol), and 0.05 equiv. of imidazole (30 mg, 0.43 mmol) in CH2Cl2 (30 ml) at room temperature for *ca*. 24 hours (until TLC analysis showed no more starting material). After addition of 25 ml of water and extraction with 3–30 ml of CH2Cl2, the organic layer was dried. After evaporation of the solvent under reduced pressure, the residue was purified by column chromatography using petroleum ether/ethyl acetate as the eluent yielded the title compound (1.94 g, 10.42 mmol, 85%) as a colorless syrup. <sup>1</sup>

(300 MHz, CDCl3): δ 6.0–5.82 (m, 2H, 〓CH), 5.42 (d, *J* = 6.5 Hz, 1H, CH),4.50 (brs, 1H, OH), 4.20–4.12(m,1H, CH), 3.91–3.80(m,4H, CH2), 0.98 (s, 9H, t-Bu), 0.24 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ 127.5, 125.6, 84.6, 81.5, 73.6, 62.7,

85:15) to afford propargyl ether as colorless oil (0.345 g, 75%). 1

*tert-butyldimethyl(((2R,3S)-3-(prop-2-ynyloxy)-3,6-dihydro-2H-pyran-2-yl) methoxy)silane* **(5)**: To a solution of alcohol **4** (400 mg, 1.63 mmol, 1.0 equiv) in toluene (1.6 ml) was added a 35% aqueous solution of NaOH (1.6 ml), propargyl bromide (80% solution in toluene, 363 μl, 2.4 mmol, 1.5 equiv), and *n*-Bu4NHSO4 (280 mg, 0.82 mmol, 0.5 equiv). After 6 hours of vigorous stirring at room temperature, Et2NH (1.6 ml) was added. The reaction mixture was stirred for 1 hour, poured into ice water, cautiously neutralized by addition of a 3 M solution of hydrochloric acid, and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (hexane/EtOAc

+Na) 267. Anal. Calcd for C12H24O3Si: C, 58.97; H, 9.90;

HNMR and 13C NMR spectra were

H and 75 MHz for 13C).

HNMR (300 MHz,

HNMR

HNMR (300 MHz,

+H) 215. Anal. Calcd for C10H14O5: C,

*DOI: http://dx.doi.org/10.5772/intechopen.86977*

catalytic reactor (ZZKD, WBFY-201). The <sup>1</sup>

recorded on a Varian Gemini spectrometer (300 MHz for <sup>1</sup>

95%) as a colorless syrup. **[α]D20**: +115.5 (*c* = 1.00, CHCl3).1

125.8, 73.6, 65.1, 64.0, 62.5, 21.1; MS: m/z (M<sup>+</sup>

56.07; H, 6.59; Found: C, 55.82; H, 6.35.

25.6, 18.1; MS: m/z (M+

Found: C, 58.62; H, 9.75.

*Synthesis and Biological Evaluation of Novel Phosphonyl Thiazolo Pyrazoles DOI: http://dx.doi.org/10.5772/intechopen.86977*

*Heterocycles - Synthesis and Biological Activities*

**3. Nematicidal activity**

the compounds were subject to nematicidal activity testing.

**Compound LD50 value (***ppm***)**

**11a** 740 860 **11b** 220 280 **11c** 320 270 **11d** 501 540 **11e** 960 900 **11f** 209 210 **11g** 310 360 Levamisole 160 180

acetonitrile afforded compound **8**. Subsequently one pot synthesis of triazole linked thiazolidinone glycosides was carried out by the condensation reaction between **8**, primary aromatic amine and a thio glycolic acid in presence of ZnCl2 under microwave irradiation (**Figure 1**). The reaction is completed in only 5–10 minutes and the compounds, isolated by conventional work-up, (**9a–g**) are obtained in satisfactory yields, Compound **9a–g** was then reacted with *p*-fluoro benzaldehyde in presence of anhydrous NaOAc in glacial AcOH at reflux temperature gave chalcone derivatives of triazole linked thiazolidinone glycosides **10a–g**, on cyclocondensation under conventional and microwave irradiation with Bestmann-Ohira reagent in presence of anhydrous KOH gave compounds **11(a–g)**. The structures of synthesized compounds were confirmed by IR, NMR, MS and elemental analysis. Further

The compounds synthesized **10a-g** in this study were also screened for their nematicidal activity against *Dietylenchus myceliophagus* and *Caenorhabditis elegans* by aqueous *in vitro* screening technique [70] at various concentrations. The nematicidal activity of each test compound was compared with the standard drug *Levamisole*. The results have been expressed in terms of LD50 i.e., median lethal dose at which 50% nematodes became immobile (dead). The screened data reveal that, compounds **11b**, **11c**, **11f** and **11g** are the most effective against *Dietylenchus myceliophagus* and *Caenorhabditis elegans* the other test compounds showed moderate activity. The LD50 values of the test compounds screened are presented in **Table 1**.

*D. myceliophagus C. elegans*

Commercial grade reagents were used as supplied. Solvents except analytical reagent grade were dried and purified according to literature when necessary. Di-methyl 2-oxopropyl phosphonate was purchased from Aldrich for the synthesis o Bestmann-Ohira reagent. Reaction progress and purity of the compounds were checked by thin-layer chromatography (TLC) on pre-coated silica gel F254 plates from Merck and compounds visualized either by exposure to UV light or dipping in 1% aqueous potassium permanganate solution. Silica gel chromatographic columns

**120**

**4. Experimental**

*Nematicidal activity of 11(a–g).*

**Table 1.**

(60–120 mesh) were used for separations. Optical rotations were measured on a Perkin-Elmer 141 polarimeter by using a 2 ml cell with a path length of 1 dm with CHCl3 or CDCl3 as solvent. All melting points are uncorrected and measured using Fisher-Johns apparatus. IR spectra were recorded as KBr disks on a Perkin-Elmer FTIR spectrometer. Micro wave reactions are carried out in mini lab microwave catalytic reactor (ZZKD, WBFY-201). The <sup>1</sup> HNMR and 13C NMR spectra were recorded on a Varian Gemini spectrometer (300 MHz for <sup>1</sup> H and 75 MHz for 13C). Chemical shifts are reported as δ ppm against TMS as internal reference and coupling constants (*J*) are reported in Hz units. Mass spectra were recorded on a VG micro mass 7070H spectrometer. Elemental analysis (C, H, N) determined by a Perkin-Elmer 240 CHN elemental analyzer, were within ±0.4% of theoretical.

*((2R,3S)-3-acetoxy-3,6-dihydro-2H-pyran-2-yl)methyl acetate* **(2)**: Tri-*O*acetyl-D-glucal (**1**) (3.0 g, 11.02 mmol) was dissolved in anhydrous dichloromethane (5 ml). The solution was cooled to 0°C, triethyl silane (1.53 g, 13.22 mmol) was added and the mixture was stirred for 5 minutes. Next boron tri fluoride diethyl etherate (690 μl of a 40 w% solution in diethyl ether, 11.02 mmol) was added drop wise and the reaction mixture was stirred for 90 minutes. The mixture was poured into a saturated solution of NaHCO3. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure. Column chromatography on silica gel (PE/EtOAc, 3:1) yielded the title compound (2.24 g, 10.42 mmol, 95%) as a colorless syrup. **[α]D20**: +115.5 (*c* = 1.00, CHCl3).1 HNMR (300 MHz, CDCl3): δ 5.87-5.84 (m, 2H, =CH),4.95 (t,1H, OCH),4.03-3.99 (m, 1H, CH),4.12- 4.09 (m,4H, OCH2), 2.20 (s, 6H, COCH3);13C NMR (75 MHz, CDCl3): δ170.2, 127.2, 125.8, 73.6, 65.1, 64.0, 62.5, 21.1; MS: m/z (M<sup>+</sup> +H) 215. Anal. Calcd for C10H14O5: C, 56.07; H, 6.59; Found: C, 55.82; H, 6.35.

**(2R,3S)-2-((tert-butyldimethylsilyloxy)methyl)-3,6-dihydro-2H-pyran-3-ol (4)**: Diacetate **2** (17.22 mmol) was treated by a catalytic amount of sodium methoxide in methanol (100 ml) at room temperature. After evaporation of the solvent, the free hydroxyl unsaturated glycoside was obtained in quantitative yield and used without further purification. This diol was treated with 2.50 equiv. of TBD MSCl (3.14 g, 21.14 mmol), 2.6 equiv. of NEt3 (3.2 ml, 22.4 mmol), and 0.05 equiv. of imidazole (30 mg, 0.43 mmol) in CH2Cl2 (30 ml) at room temperature for *ca*. 24 hours (until TLC analysis showed no more starting material). After addition of 25 ml of water and extraction with 3–30 ml of CH2Cl2, the organic layer was dried. After evaporation of the solvent under reduced pressure, the residue was purified by column chromatography using petroleum ether/ethyl acetate as the eluent yielded the title compound (1.94 g, 10.42 mmol, 85%) as a colorless syrup. <sup>1</sup> HNMR (300 MHz, CDCl3): δ 6.0–5.82 (m, 2H, 〓CH), 5.42 (d, *J* = 6.5 Hz, 1H, CH),4.50 (brs, 1H, OH), 4.20–4.12(m,1H, CH), 3.91–3.80(m,4H, CH2), 0.98 (s, 9H, t-Bu), 0.24 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ 127.5, 125.6, 84.6, 81.5, 73.6, 62.7, 25.6, 18.1; MS: m/z (M+ +Na) 267. Anal. Calcd for C12H24O3Si: C, 58.97; H, 9.90; Found: C, 58.62; H, 9.75.

*tert-butyldimethyl(((2R,3S)-3-(prop-2-ynyloxy)-3,6-dihydro-2H-pyran-2-yl) methoxy)silane* **(5)**: To a solution of alcohol **4** (400 mg, 1.63 mmol, 1.0 equiv) in toluene (1.6 ml) was added a 35% aqueous solution of NaOH (1.6 ml), propargyl bromide (80% solution in toluene, 363 μl, 2.4 mmol, 1.5 equiv), and *n*-Bu4NHSO4 (280 mg, 0.82 mmol, 0.5 equiv). After 6 hours of vigorous stirring at room temperature, Et2NH (1.6 ml) was added. The reaction mixture was stirred for 1 hour, poured into ice water, cautiously neutralized by addition of a 3 M solution of hydrochloric acid, and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (hexane/EtOAc 85:15) to afford propargyl ether as colorless oil (0.345 g, 75%). 1 HNMR (300 MHz,

CDCl3): δ 6.03–5.80 (m, 2H, 〓CH), 4.69 (t, *J* = 3.9 Hz 1H, CH), 3.68 (dd, *J* = 8.9 Hz, 4.1 Hz, 1H, OCH), 3.99–3.89(m, 6H, CH2), 3.20 (s, 1H, CH), 0.96 (s, 9H, t-Bu), 0.23 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ 127.2, 124.9, 78.0, 76.2, 74.2, 64.2, 63.2, 58.5, 25.3, 18.5; MS: m/z (M+ +H) 283. Anal. Calcd for C15H26O3Si: C, 63.78; H, 9.28; Found: C, 63.62; H, 8.95.

*((2R,3S)-3-(prop-2-ynyloxy)-3,6-dihydro-2H-pyran-2-yl)methanol* **(6)**: To a stirred solution of 5 (0.325 g) in Tetra hydro furan catalytic amount of TBAF was added and stirred the reaction mixture at room temperature for 15 minutes, extracted the product with Ethyl acetate (20 ml). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (60–120 mesh, hexane/EtOAc 70, 0) to afford alcohol as yellow oil (0.285 g, 85%) 1 HNMR (300 MHzCDCl3) 5.95–5.75 (m, 2H, 〓CH), 4.65(d, *J* = 3.9 Hz, 1H, CH), 4.52 (brs, 1H, OH), 4.09–4.11 (m, 4H, OCH2), 3.64 (dd, *J* = 4.1 Hz, 8.9 Hz, 1H, OCH), 3.76 (d, *J* = 6.8 Hz, 2H, OCH2), 3.28 (s, 1H, CH): 13C NMR (75 MHz, CDCl3): δ 127.2, 125.6, 78.3, 76.1, 74.1, 64.2, 61.4, 58.0; MS: m/z (M+ +H) 169. Anal. Calcd for C9H12O3: C, 64.27; H, 7.10; Found: C, 64.02; H, 6.95.

*((2R,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)methanol* **(7)**: To a solution containing alkyne **6** (0.250 g, 0.778 mmol), p-chloro phenyl azide (0.130 g, 0.849 mmol) in dichloromethane (10 ml) and water (10 ml) were added CuSO4.5H2O (0.110 g) and sodium ascorbate (0.114 g). The resulting suspension was stirred at room temperature for 6 hours. After this time, the mixture was diluted with 5 ml dichloromethane and 5 ml water. The organic phase was separated, dried with sodium sulfate and concentrated at reduced pressure the crude product was purified by column chromatography on silica gel (60–120 mesh, hexane/EtOAc 65:35) to afford **7** (0.290 g, 75%) as a white powder. Mp: 149–1510°C. 1 HNMR (300 MHz, CDCl3): δ8.05 (s, 1H, Ar-H), 7.56 (d, *J* = 9.2 Hz, 2H, Ar-H),7.45 (d, *J* = 8.9 Hz, 2H, Ar-H), 5.85–5.79 (m, 2H, 〓CH), 4.59 (s, 2H, OCH2), 4.50 (brs, 1H, OH), 3.88–3.99 (m, 4H, OCH2), 3.8–3.75 (m, 2H, OCH): 13CNMR (75 MHz, CDCl3): δ140.9, 134.5, 134.1, 128.4, 127.5, 125.4, 122.1, 11.5, 78.6, 68.5, 65.7, 64.2, 62.4: MS: m/z (M+ +H) 322. Anal. Calcd for C15H16ClN3O3: C, 55.90; H, 5.01, N, 13.06; Found: C, 55.65, H, 4.95. N, 12.86.

*(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-3-phenylthiazolidin-4-one* **9(a-g)**: To a solution of alcohol **7** (0.120 g, 0.465 mmol) in CH2Cl2 (5 ml), catalytic amount of IBX was added at 0°C and stirred at room temperature for 30 minutes. The reaction mixture was filtered and washed with CH2Cl2 (2 × 10 ml). It was dried (Na2SO4) and evaporated to give aldehyde 7 (0.110 g) in quantitative yield as a yellow liquid, which was used as such for the next reaction.

To a stirred mixture of **8** (0.110 g, 0.373 mmol), aromatic amine (0.373 mmol) and anhydrous thioglycolic acid (0.140 g, 0.211 mmol) in dry toluene (5 ml), ZnCl2 (0.100 g, 0.751 mmol) was added after 2 minutes and irradiated in microwave bath reactor at 280 W for 4–7 minutes at 110°C. After cooling, the filtrate was concentrated to dryness under reduced pressure and the residue was taken-up in ethyl acetate. The ethyl acetate layer was washed with 5% sodium bicarbonate solution and finally with brine. The organic layer was dried over Na2SO4 and evaporated to dryness at reduced pressure. The crude product thus obtained was purified by column chromatography on silica gel (60–120 mesh) with hexaneethyl acetate as eluent.

(*R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl) methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-phenylthiazolidin-4-one* **(9a)**: mp: 157–159°C. Yield—75%. <sup>1</sup> HNMR (300 MHz, CDCl3): δ8.04 (s, 1H, Ar-H), 7.50

**123**

*Synthesis and Biological Evaluation of Novel Phosphonyl Thiazolo Pyrazoles*

(d, *J* = 9.2 Hz, 2H, Ar-H), 7.40 (d, *J* = 8.9 Hz, 2H, Ar-H), 7.10–6.20 (m, 5H, Ar-H), 5.80–5.71 (m, 2H, 〓CH), 4.90 (d, *J* = 5.2 Hz, 1H, CH-S), 4.52 (s, 2H, OCH2), 4.09–3.94 (m, 2XCH), 3.79 (d, *J* = 6.6 Hz, 2H, OCH2), 3.72 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ170.4, 144.1, 141.8, 134.1, 128.2, 125.6, 122.4, 119.4, 85.6, 72.6,

(*R)-3-(4-chlorophenyl)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3 triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)thiazolidin-4-one* **(9b)**: mp:

129.2, 125.5, 122.2, 119.4, 85.4, 72.8, 65.4, 63.4, 51.2, 34.1: MS: m/z (M+

*J* = 9.4 Hz, 4H, Ar-H), 7.42 (d, *J* = 8.6 Hz, 4H, Ar-H), 5.84–5.75 (m, 2H, 〓CH), 4.94 (d, *J* = 5.2 Hz, CH-S), 4.50 (s, 2H, OCH2), 4.06–3.96 (m, 2H, 2XCH), 3.80 (t, 2H, OCH2), 3.72 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ 170.5, 144.2, 139.2, 134.2,

Anal. Calcd for C23H20Cl2N4O3S: C, 54.88; H, 4.00, N, 11.13; Found: C, 54.58, H,

*(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-3-(4-nitrophenyl)thiazolidin-4-one* **(9c)**: mp:

8.03 (s, 1H, Ar-H), 7.61 (d, *J* = 9.4 Hz, 2H, Ar-H), 7.46 (d, *J* = 8.5 Hz, 2H, Ar-H), 6.84 (d, *J* = 9.8 Hz, 2H, Ar-H), 5.86–5.79 (m, 2H, 〓CH), 4.96 (d, *J* = 5.2 Hz, CH-S), 4.55 (s, 2H, OCH2), 4.05–3.95 (m, 2H, 2XCH), 3.85 (d, *J* = 6.9 Hz, 2H, OCH2), 3.82 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ171.5, 144.0, 141.8, 134.2, 128.5, 125.4, 119.5, 85.4,

*(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-o-tolylthiazolidin-4-one* **(9d)**: mp: 191–193°C, Yield—65%.

HNMR (300 MHz, CDCl3): δ8.08 (s, 1H, Ar-H), 7.56 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.49 (d, *J* = 8.7 Hz, 2H, Ar-H), 7.45–7.39 (m, 4H, Ar-H), 5.76 (m, 2H, 〓CH), 4.93 (d, *J* = 5.2 Hz, 1H, CHS), 4.60 (s, 2H, OCH2), 4.05–3.96 (m, 2H, CH), 3.90 (t, 2H, OCH2), 3.81 (s, 2H, CH2), 2.1 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.5, 144.2, 138.2, 134.2, 130.7, 128.6, 125.6, 122.0, 119.5, 116.5, 85.4, 72.6, 65.8, 63.4, 52.0, 32.3, 17.5: MS: m/z

+H) 483. Anal. Calcd for C24H23ClN4O3S: C, 59.68; H, 4.80, N, 11.60; Found: C,

*(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-3-p-tolylthiazolidin-4-one* **(9e)**: mp: 195–198°C

Anal. Calcd for C24H23ClN4O3S: C, 59.68; H, 4.80, N, 11.60; Found: C, 59.58, H, 4.65.

(s, 1H, Ar-H), 7.58 (d, *J* = 9.3 Hz, 2H, Ar-H), 7.49 (d, *J* = 8.6 Hz, 2H, Ar-H), 6.83–6.76 (m, 4H, Ar-H), 5.72–5.68 (m, 2H, 〓CH), 4.94 (d, J = 5.2 Hz, 1H, CHS), 4.64 (s, 2H, OCH2), 4.12 (t, 2H, OCH2), 4.01–3.94 (m, 2H, CH), 3.92 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ 170.5, 158.2, 143.8, 134.5, 130.4, 128.6, 125.6, 122.4, 119.5,

C23H21ClN4O4S: C, 59.96; H, 4.36, N, 11.55; Found: C, 59.28, H, 4.65. N, 11.43.

114.8, 106.5, 85.4, 72.5, 66.4, 63.4, 51.5, 34.1: MS: m/z (M+

*(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-3-(3-hydroxyphenyl)thiazolidin-4-one* **(9f)**: mp:

2H, Ar-H), 7.45 (d, *J* = 8.7 Hz, 2H, Ar-H), 7.25 (d, *J* = 8.2 Hz, 2H, Ar-H), 6.84 (d, *J* = 9.4 Hz, 2H, Ar-H), 5.72–5.68 (m, 2H, 〓CH), 4.95 (s, 1H, CHS), 4.59 (s, 2H, OCH2), 4.04–3.99 (m, 2H, CH), 3.98 (t, 2H, OCH2), 3.90 (s, 2H, CH2), 2.32 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.5, 144.2, 138.6, 136.2, 14.1, 133.2, 129.4, 127.5, 122.5, 119.5, 85.4, 72.0, 66.4, 63.5, 51.5, 34.0, 21.4: MS: m/z (M+

HNMR (300 MHz, CDCl3): δ8.05 (s, 1H, Ar-H), 7.51 (d, *J* = 9.2 Hz,

H-NMR (300 MHz, CDCl3): δ9.40 (brs, 1H, Ph-OH), 8.08

+H) 469. Anal. Calcd for C23H21ClN4O3S: C, 58.91;

+Na) 525.

+H) 483.

+Na) 507. Anal. Calcd for

HNMR (300 MHz, CDCl3): 8.05 (s, 1H, Ar-H), 7.54 (d,

HNMR (300 MHz, CDCl3): δ8.26 (d, *J* = 8.7 Hz, 2H, Ar-H),

+H) 514. Anal. Calcd for C23H20ClN5O5S:

*DOI: http://dx.doi.org/10.5772/intechopen.86977*

H, 4.51, N, 11.95; Found: C, 58. 68, H, 4.35. N, 11.66.

66.4, 64.0, 51.4, 33.9: MS: m/z (M+

226–228°C Yield—69%. 1

211–213°C, Yield—71%. 1

59.48, H, 4.55. N, 11.49.

218–219°C, Yield—85%. 1

Yield—79%. <sup>1</sup>

N, 11.43.

72.4, 65.9, 63.6, 51.5, 34.6: MS: m/z (M+

C, 53.75; H, 3.92, N, 13.63; Found: C, 53.58, H, 3.75. N, 13.39.

3.75. N, 10.86.

1

(M+

*Heterocycles - Synthesis and Biological Activities*

125.6, 78.3, 76.1, 74.1, 64.2, 61.4, 58.0; MS: m/z (M+

C, 64.27; H, 7.10; Found: C, 64.02; H, 6.95.

58.5, 25.3, 18.5; MS: m/z (M+

Found: C, 63.62; H, 8.95.

powder. Mp: 149–1510°C. 1

68.5, 65.7, 64.2, 62.4: MS: m/z (M+

used as such for the next reaction.

ethyl acetate as eluent.

157–159°C. Yield—75%. <sup>1</sup>

5.01, N, 13.06; Found: C, 55.65, H, 4.95. N, 12.86.

1

CDCl3): δ 6.03–5.80 (m, 2H, 〓CH), 4.69 (t, *J* = 3.9 Hz 1H, CH), 3.68 (dd, *J* = 8.9 Hz, 4.1 Hz, 1H, OCH), 3.99–3.89(m, 6H, CH2), 3.20 (s, 1H, CH), 0.96 (s, 9H, t-Bu), 0.23 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ 127.2, 124.9, 78.0, 76.2, 74.2, 64.2, 63.2,

*((2R,3S)-3-(prop-2-ynyloxy)-3,6-dihydro-2H-pyran-2-yl)methanol* **(6)**: To a stirred solution of 5 (0.325 g) in Tetra hydro furan catalytic amount of TBAF was added and stirred the reaction mixture at room temperature for 15 minutes, extracted the product with Ethyl acetate (20 ml). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (60–120 mesh, hexane/EtOAc 70, 0) to afford alcohol as yellow oil (0.285 g, 85%)

HNMR (300 MHzCDCl3) 5.95–5.75 (m, 2H, 〓CH), 4.65(d, *J* = 3.9 Hz, 1H, CH), 4.52 (brs, 1H, OH), 4.09–4.11 (m, 4H, OCH2), 3.64 (dd, *J* = 4.1 Hz, 8.9 Hz, 1H, OCH), 3.76 (d, *J* = 6.8 Hz, 2H, OCH2), 3.28 (s, 1H, CH): 13C NMR (75 MHz, CDCl3): δ 127.2,

*((2R,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)methanol* **(7)**: To a solution containing alkyne **6** (0.250 g, 0.778 mmol), p-chloro phenyl azide (0.130 g, 0.849 mmol) in dichloromethane (10 ml) and water (10 ml) were added CuSO4.5H2O (0.110 g) and sodium ascorbate (0.114 g). The resulting suspension was stirred at room temperature for 6 hours. After this time, the mixture was diluted with 5 ml dichloromethane and 5 ml water. The organic phase was separated, dried with sodium sulfate and concentrated at reduced pressure the crude product was purified by column chromatography on silica gel (60–120 mesh, hexane/EtOAc 65:35) to afford **7** (0.290 g, 75%) as a white

*J* = 9.2 Hz, 2H, Ar-H),7.45 (d, *J* = 8.9 Hz, 2H, Ar-H), 5.85–5.79 (m, 2H, 〓CH), 4.59 (s, 2H, OCH2), 4.50 (brs, 1H, OH), 3.88–3.99 (m, 4H, OCH2), 3.8–3.75 (m, 2H, OCH): 13CNMR (75 MHz, CDCl3): δ140.9, 134.5, 134.1, 128.4, 127.5, 125.4, 122.1, 11.5, 78.6,

*(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-3-phenylthiazolidin-4-one* **9(a-g)**: To a solution of alcohol **7** (0.120 g, 0.465 mmol) in CH2Cl2 (5 ml), catalytic amount of IBX was added at 0°C and stirred at room temperature for 30 minutes. The reaction mixture was filtered and washed with CH2Cl2 (2 × 10 ml). It was dried (Na2SO4) and evaporated to give aldehyde 7 (0.110 g) in quantitative yield as a yellow liquid, which was

To a stirred mixture of **8** (0.110 g, 0.373 mmol), aromatic amine (0.373 mmol)

and anhydrous thioglycolic acid (0.140 g, 0.211 mmol) in dry toluene (5 ml), ZnCl2 (0.100 g, 0.751 mmol) was added after 2 minutes and irradiated in microwave bath reactor at 280 W for 4–7 minutes at 110°C. After cooling, the filtrate was concentrated to dryness under reduced pressure and the residue was taken-up in ethyl acetate. The ethyl acetate layer was washed with 5% sodium bicarbonate solution and finally with brine. The organic layer was dried over Na2SO4 and evaporated to dryness at reduced pressure. The crude product thus obtained was purified by column chromatography on silica gel (60–120 mesh) with hexane-

(*R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)*

*methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-phenylthiazolidin-4-one* **(9a)**: mp:

HNMR (300 MHz, CDCl3): δ8.04 (s, 1H, Ar-H), 7.50

+H) 283. Anal. Calcd for C15H26O3Si: C, 63.78; H, 9.28;

HNMR (300 MHz, CDCl3): δ8.05 (s, 1H, Ar-H), 7.56 (d,

+H) 322. Anal. Calcd for C15H16ClN3O3: C, 55.90; H,

+H) 169. Anal. Calcd for C9H12O3:

**122**

(d, *J* = 9.2 Hz, 2H, Ar-H), 7.40 (d, *J* = 8.9 Hz, 2H, Ar-H), 7.10–6.20 (m, 5H, Ar-H), 5.80–5.71 (m, 2H, 〓CH), 4.90 (d, *J* = 5.2 Hz, 1H, CH-S), 4.52 (s, 2H, OCH2), 4.09–3.94 (m, 2XCH), 3.79 (d, *J* = 6.6 Hz, 2H, OCH2), 3.72 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ170.4, 144.1, 141.8, 134.1, 128.2, 125.6, 122.4, 119.4, 85.6, 72.6, 66.4, 64.0, 51.4, 33.9: MS: m/z (M+ +H) 469. Anal. Calcd for C23H21ClN4O3S: C, 58.91; H, 4.51, N, 11.95; Found: C, 58. 68, H, 4.35. N, 11.66.

(*R)-3-(4-chlorophenyl)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3 triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)thiazolidin-4-one* **(9b)**: mp: 226–228°C Yield—69%. 1 HNMR (300 MHz, CDCl3): 8.05 (s, 1H, Ar-H), 7.54 (d, *J* = 9.4 Hz, 4H, Ar-H), 7.42 (d, *J* = 8.6 Hz, 4H, Ar-H), 5.84–5.75 (m, 2H, 〓CH), 4.94 (d, *J* = 5.2 Hz, CH-S), 4.50 (s, 2H, OCH2), 4.06–3.96 (m, 2H, 2XCH), 3.80 (t, 2H, OCH2), 3.72 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ 170.5, 144.2, 139.2, 134.2, 129.2, 125.5, 122.2, 119.4, 85.4, 72.8, 65.4, 63.4, 51.2, 34.1: MS: m/z (M+ +Na) 525. Anal. Calcd for C23H20Cl2N4O3S: C, 54.88; H, 4.00, N, 11.13; Found: C, 54.58, H, 3.75. N, 10.86.

*(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-3-(4-nitrophenyl)thiazolidin-4-one* **(9c)**: mp: 211–213°C, Yield—71%. 1 HNMR (300 MHz, CDCl3): δ8.26 (d, *J* = 8.7 Hz, 2H, Ar-H), 8.03 (s, 1H, Ar-H), 7.61 (d, *J* = 9.4 Hz, 2H, Ar-H), 7.46 (d, *J* = 8.5 Hz, 2H, Ar-H), 6.84 (d, *J* = 9.8 Hz, 2H, Ar-H), 5.86–5.79 (m, 2H, 〓CH), 4.96 (d, *J* = 5.2 Hz, CH-S), 4.55 (s, 2H, OCH2), 4.05–3.95 (m, 2H, 2XCH), 3.85 (d, *J* = 6.9 Hz, 2H, OCH2), 3.82 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ171.5, 144.0, 141.8, 134.2, 128.5, 125.4, 119.5, 85.4, 72.4, 65.9, 63.6, 51.5, 34.6: MS: m/z (M+ +H) 514. Anal. Calcd for C23H20ClN5O5S: C, 53.75; H, 3.92, N, 13.63; Found: C, 53.58, H, 3.75. N, 13.39.

*(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-o-tolylthiazolidin-4-one* **(9d)**: mp: 191–193°C, Yield—65%. 1 HNMR (300 MHz, CDCl3): δ8.08 (s, 1H, Ar-H), 7.56 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.49 (d, *J* = 8.7 Hz, 2H, Ar-H), 7.45–7.39 (m, 4H, Ar-H), 5.76 (m, 2H, 〓CH), 4.93 (d, *J* = 5.2 Hz, 1H, CHS), 4.60 (s, 2H, OCH2), 4.05–3.96 (m, 2H, CH), 3.90 (t, 2H, OCH2), 3.81 (s, 2H, CH2), 2.1 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.5, 144.2, 138.2, 134.2, 130.7, 128.6, 125.6, 122.0, 119.5, 116.5, 85.4, 72.6, 65.8, 63.4, 52.0, 32.3, 17.5: MS: m/z (M+ +H) 483. Anal. Calcd for C24H23ClN4O3S: C, 59.68; H, 4.80, N, 11.60; Found: C, 59.48, H, 4.55. N, 11.49.

*(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-3-p-tolylthiazolidin-4-one* **(9e)**: mp: 195–198°C Yield—79%. <sup>1</sup> HNMR (300 MHz, CDCl3): δ8.05 (s, 1H, Ar-H), 7.51 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.45 (d, *J* = 8.7 Hz, 2H, Ar-H), 7.25 (d, *J* = 8.2 Hz, 2H, Ar-H), 6.84 (d, *J* = 9.4 Hz, 2H, Ar-H), 5.72–5.68 (m, 2H, 〓CH), 4.95 (s, 1H, CHS), 4.59 (s, 2H, OCH2), 4.04–3.99 (m, 2H, CH), 3.98 (t, 2H, OCH2), 3.90 (s, 2H, CH2), 2.32 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.5, 144.2, 138.6, 136.2, 14.1, 133.2, 129.4, 127.5, 122.5, 119.5, 85.4, 72.0, 66.4, 63.5, 51.5, 34.0, 21.4: MS: m/z (M+ +H) 483. Anal. Calcd for C24H23ClN4O3S: C, 59.68; H, 4.80, N, 11.60; Found: C, 59.58, H, 4.65. N, 11.43.

*(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-3-(3-hydroxyphenyl)thiazolidin-4-one* **(9f)**: mp: 218–219°C, Yield—85%. 1 H-NMR (300 MHz, CDCl3): δ9.40 (brs, 1H, Ph-OH), 8.08 (s, 1H, Ar-H), 7.58 (d, *J* = 9.3 Hz, 2H, Ar-H), 7.49 (d, *J* = 8.6 Hz, 2H, Ar-H), 6.83–6.76 (m, 4H, Ar-H), 5.72–5.68 (m, 2H, 〓CH), 4.94 (d, J = 5.2 Hz, 1H, CHS), 4.64 (s, 2H, OCH2), 4.12 (t, 2H, OCH2), 4.01–3.94 (m, 2H, CH), 3.92 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ 170.5, 158.2, 143.8, 134.5, 130.4, 128.6, 125.6, 122.4, 119.5, 114.8, 106.5, 85.4, 72.5, 66.4, 63.4, 51.5, 34.1: MS: m/z (M+ +Na) 507. Anal. Calcd for C23H21ClN4O4S: C, 59.96; H, 4.36, N, 11.55; Found: C, 59.28, H, 4.65. N, 11.43.

*(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-(4-hydroxyphenyl)thiazolidin-4-one* **(9g)**: mp: 273–275°C, Yield—82%. 1 H-NMR (300 MHz, CDCl3): δ9.42 (brs, 1H, Ph-OH), 8.05 (s, 1H, Ar-H), 7.56 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.46 (d, *J* = 8.4 Hz, 2H, Ar-H), 7.32 (d, *J* = 8.6 Hz, 2H, Ar-H), 7.02 (d, *J* = 8.8 Hz, 2H, Ar-H), 5.89–5.80 (m, 2H, 〓CH), 4.96 (d, *J* = 5.4 Hz, 1H, CHS), 4.66 (s, 2H, OCH2), 4.09 (d, *J* = 2H, OCH2), 4.04–3.98 (m, 2H, CH), 3.94 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ170.9, 154.1, 144.4, 134.9, 134.8, 128.8, 127.2, 125.6, 123.2, 119.4, 116.4, 85.4, 72.6, 66.5, 64.0, 51.6, 34.5: MS: m/z (M+ +H) 485. Anal. Calcd for C23H21ClN4O4S: C, 59.96; H, 4.36, N, 11.55; Found: C, 59.38, H, 4.75. N, 11.33.

**General procedure for the synthesis of (10a-g)**: A mixture of compound **9a** (0.01 mol), *p*-fluoro benzaldehyde (0.02 mol) and sodium acetate (0.01 mol) in anhydrous glacial acetic acid (20 ml), was refluxed for 3 hours. The reaction mixture was concentrated and then poured into ice cold water, the solid thus separated, was filtered, washed with water and crystallized from glacial acetic acid. To afford pure **10a** as yellow solid.

*(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-phenylthiazolidin-4-one* **(10a)**: mp: 235–237°C, Yield—85%. 1 HNMR (300 MHz, CDCl3): δ8.07 (s, 1H, Ar-H), 7.80 (s, 1H, CH〓C), 7.72 (d, *J* = 9.6 Hz, 2H, Ar-H), 7.40 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.45 (d, *J* = 8.9 Hz, 2H, Ar-H), 7.19 (d, *J* = 8.2 Hz, 2H, Ar-H), 7.02–6.80 (m, 5H, Ar-H), 5.80–5.74 (m, 2H, 〓CH), 4.90 (d, *J* = 5.2 Hz, 1H, CH▬S), 4.52 (s, 2H, OCH2), 4.09–3.94 (m, 2H, 2XCH), 3.79 (d, *J* = 6.6 Hz, 2H, OCH2): 13CNMR (75 MHz, CDCl3): δ170.4, 162.1, 144.1, 141.8, 139.8, 134.1, 130.4, 128.2, 125.6, 124.6, 122.4, 119.4, 115.5, 85.6, 72.6, 66.4, 64.0, 51: MS: m/z (M+ +H) 575. Anal. Calcd for C30H24ClFN4O3S: C, 62.66; H, 4.21, N, 9.74; Found: C, 62. 48, H, 4.15. N, 9.56.

*(R,Z)-3-(4-chlorophenyl)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3 triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene) thiazolidin-4-one* **(10b)**: mp: 216–218°C. Yield—72%. 1 HNMR (300 MHz, CDCl3): 8.09 (s, 1H, Ar-H), 7.75 (s, 1H, CH〓C), 7.62 (d, *J* = 9.5 Hz, 2H, Ar-H), 7.52 (d, *J* = 9.4 Hz, 4H, Ar-H), 7.40 (d, *J* = 8.6 Hz, 4H, Ar-H), 7.19 (d, *J* = 8.1 Hz, 2H, Ar-H), 5.84–5.75 (m, 2H, 〓CH), 4.94 (d, *J* = 5.2 Hz, 1H, CH-S), 4.52 (s, 2H, OCH2), 4.06– 3.94 (m, 2H, 2XCH), 3.80 (t, 2H, OCH2): 13CNMR (75 MHz, CDCl3): δ170.5, 162.1, 144.2, 139.2, 134.2, 130.4, 129.2, 125.5, 124.1, 122.2, 119.4, 85.4, 72.8, 65.4, 63.4, 51.2: MS:m/z(M+ +Na)632. Anal. Calcd for C30H23Cl2 FN4O3S: C, 59.12; H, 3.80, N, 9.19; Found: C, 59.01, H, 3.45. N, 8.96.

*(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-(4-nitrophenyl) thiazolidin-4-one* **(10c)**: mp: 221–223°C Yield—75%. 1 HNMR (300 MHz, CDCl3): δ8.29 (d, *J* = 8.7 Hz, 2H, Ar-H), 8.09 (s, 1H, Ar-H), 7.69 (d, *J* = 9.1 Hz, 2H, Ar-H), 7.65 (s, 1H, CH〓C), 7.61 (d, *J* = 9.4 Hz, 2H, Ar-H), 7.46 (d, *J* = 8.5 Hz, 2H, Ar-H), 7.18 (d, *J* = 8.3 Hz, 2H, Ar-H), 6.84 (d, *J* = 9.8 Hz, 2H, Ar-H), 5.86–5.79 (m, 2H, 〓CH), 4.96 (d, *J* = 5.2 Hz, CH-S), 4.55 (s, 2H, OCH2), 4.05–3.95 (m, 2H, 2XCH), 3.85 (d, *J* = 6.9 Hz, 2H, OCH2): 13CNMR (75 MHz, CDCl3): δ171.5, 162.1, 144.0, 141.8, 134.2, 130.4, 128.5, 125.4, 119.5, 115.4, 85.4, 72.4, 65.9, 63.6, 51.5: MS: m/z (M+ +H) 620. Calcd for C30H23ClFN5O5S: C, 58.11; H, 3.74, N, 11.29; Found: C, 57.98, H, 3.55. N, 11.09.

*(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-o-tolylthiazolidin-4-one* **(10d)**: mp: 201–203°C, Yield—85%. <sup>1</sup> HNMR (300 MHz, CDCl3): δ8.08 (s, 1H, Ar-H), 7.69 (d, *J* = 8.5 Hz, 2H, Ar-H), 7.62 (s, 1H, CH〓C), 7.56 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.49 (d, *J* = 8.7 Hz, 2H, Ar-H), 7.45–7.39 (m, 4H, Ar-H), 7.10 (d, *J* = 9.1 Hz, 2H, Ar-H), 5.76 (m, 2H, 〓CH), 4.93 (d, *J* = 5.2 Hz, 1H, CHS), 4.60 (s, 2H, OCH2), 4.05–3.96 (m, 2H, CH), 3.90 (t, 2H, OCH2), 2.1 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.8, 162.9, 144.6, 137.2, 133.2, 130.6, 130.4, 128.2,

**125**

*Synthesis and Biological Evaluation of Novel Phosphonyl Thiazolo Pyrazoles*

125.9, 122.7, 119.2, 116.2, 115.4, 84.4, 72.1, 65.3, 63.1, 52.5, 32.0, 17.5: MS: m/z

+H) 589. Anal. Calcd for C31H26ClFN4O3S: C, 63.21; H, 4.45, N, 9.51; Found: C,

HNMR (300 MHz, CDCl3): δ8.02

H-NMR (300 MHz, CDCl3): δ9.42 (brs, 1H,

+H) 591. Anal. Calcd

H-NMR (300 MHz,CDCl3):

+H) 591. Anal. Calcd for

+H) 725. Anal. Calcd for

HNMR

*(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-p-tolylthiazolidin-4-one*

(s, 1H, Ar-H), 7.69 (s, 1H, CH〓C), 7.65 (d, *J* = 9.1 Hz, 2H, Ar-H), 7.54 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.42 (d, *J* = 8.7 Hz, 2H, Ar-H), 7.35 (d, *J* = 8.2 Hz, 2H, Ar-H), 7.18 (d, *J* = 8.8 Hz, 2H, Ar-H), 6.80 (d, *J* = 9.4 Hz, 2H, Ar-H), 5.70–5.69 (m, 2H, 〓CH), 4.94 (s, 1H, CHS), 4.55 (s, 2H, OCH2), 4.04–3.98 (m, 2H, CH), 3.96 (t, 2H, OCH2), 2.32 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.1, 162.5, 144.1, 139.5, 137.6, 135.2, 133.2, 130.4, 129.1, 127.5, 124.1, 122.5, 119.5, 115.3, 85.1, 72.5, 66.1, 63.2, 51.2, 21.6:

+H) 589. Anal. Calcd for C31H26ClFN4O3S: C, 63.21; H, 4.45, N, 9.51;

*(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6 dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-(3-hydroxyphenyl)thiazolidin-*

Ph-OH), 8.08 (s, 1H, Ar-H), 7.71 (d, *J* = 9.7 Hz, 2H, Ar-H), 7.65 (s, 1H, CH〓C), 7.59 (d, *J* = 9.3 Hz, 2H, Ar-H), 7.44 (d, *J* = 8.6 Hz, 2H, Ar-H), 7.15 (d, *J* = 8.4 Hz, 2H, Ar -H), 6.80–6.78 (m, 4H, Ar-H), 5.70–5.68 (m, 2H, 〓CH), 4.92 (d, *J* = 5.2 Hz, 1H, CHS),

MHz, CDCl3): δ170.5, 162.1, 158.2, 143.8, 139.8, 134.5, 130.8, 128.6, 125.6, 124.1, 122.4,

δ9.42 (brs, 1H, Ph-OH), 8.05 (s, 1H, Ar-H), 7.85 (d, *J* = 9.3 Hz, 2H, Ar-H), 7.65 (s, 1H, CH〓C), 7.56 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.46 (d, *J* = 8.4 Hz, 2H, Ar-H), 7.32 (d, *J* = 8.6 Hz, 2H, Ar-H), 7.19 (d, *J* = 8.3 Hz, 2H, ArH), 7.02 (d, *J* = 8.8 Hz, 2H, Ar-H), 5.89–5.80 (m, 2H, 〓CH), 4.96 (d, *J* = 5.4 Hz, 1H, CHS), 4.66 (s, 2H,

OCH2), 4.09 (d, *J* = 2H, OCH2), 4.04–3.98 (m, 2H, CH), 13CNMR (75 MHz, CDCl3): δ170.9, 162.5, 154.1, 144.4, 139.8, 134.9, 134.8, 130.4, 128.8, 127.2, 125.6, 123.2,

(300 MHz, CDCl3): δ13.06 (brs, 1H, 〓NH), 8.03 (s, 1H, Ar-H), 7.70 (d, *J* = 9.6 Hz, 2H, Ar-H), 7.30 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.45 (d, *J* = 8.9 Hz, 2H, Ar-H), 7.19 (d, *J* = 8.2 Hz, 2H, Ar-H), 6.95–6.70 (m, 5H, Ar-H), 5.80–5.74 (m, 2H, 〓CH), 4.80 (d, *J* = 5.2 Hz, 1H, CH-S), 4.42 (s, 2H, OCH2), 4.09–3.94 (m, 2H, 2XCH), 3.78 (s, 6H, OCH3), 3.69 (d, *J* = 6.6 Hz, 2H, OCH2), 3.52 (s, 1H, CH): 13CNMR (75 MHz, CDCl3): δ170.1, 160.1, 155.2, 144.1, 141.6, 136.2, 134.1, 129.2, 127.5, 125.6, 122.1,

C33H31ClFN6O6PS: C, 54.66; H, 4.31, N, 11.59; Found: C, 54.48, H, 4.05. N, 11.36.

C30H24ClFN4O4S: C, 60.96; H, 4.09, N, 9.48; Found: C, 60.58, H, 3.95. N, 9.23. **General procedure for the synthesis of Pyrazole phosphonates (11a-g)**: To a stirred mixture of **10a** (1 mmol), and Bestmann-Ohira Reagent (2.5 mmol) in dry EtOH (10 ml) was added KOH (2.5 mmol) at room temperature, after 2 minutes and irradiated in microwave bath reactor at 500 W for 4–7 minutes at 50°C. The crude product thus obtained was purified by column chromatography on silica gel (60–120 mesh) with hexane-ethyl acetate as eluent. Under conventional method the reaction mixture in EtOH (10 ml) was stirred at room temperature for the appropriate time (**Table 2**). *Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-8-phenyl-6-thia-1,2,8 triazaspiro[4.4]non-2-en-3-ylphosphonate* **(11a)**: 245–247°C, Yield—75%. 1

4.64 (s, 2H, OCH2), 4.10 (t, 2H, OCH2), 4.01–3.98 (m, 2H, CH): 13CNMR (75

for C30H24ClFN4O4S: C, 60.96; H, 4.09, N, 9.48; Found: C, 60.58, H, 3.85. N, 9.13. *(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-(4-hydroxyphenyl)*

119.5, 115.7, 114.8, 106.5, 85.4, 72.5, 66.4, 63.4, 51.5: MS: m/z (M+

*thiazolidin-4-one* **(10g)**: mp: 283–285°C, Yield—62%. 1

119.4, 116.4, 115.9, 85.4, 72.6, 66.5, 64.0, 51.6: MS: m/z (M<sup>+</sup>

119.1, 115.8, 86.6, 72.9, 63.8, 53.8, 44.5, 34.9: MS: m/z (M+

*DOI: http://dx.doi.org/10.5772/intechopen.86977*

**(10e)**: mp: 205–215°C, Yield—66%. 1

Found: C, 62.98, H, 4.25. N, 9.33.

*4-one* **(10f)**: mp: 218–219°C, Yield—82%. 1

(M<sup>+</sup>

62.75, H, 4.25. N, 9.29.

MS: m/z (M+

*Heterocycles - Synthesis and Biological Activities*

Yield—82%. 1

pure **10a** as yellow solid.

**(10a)**: mp: 235–237°C, Yield—85%. 1

122.4, 119.4, 115.5, 85.6, 72.6, 66.4, 64.0, 51: MS: m/z (M+

*thiazolidin-4-one* **(10b)**: mp: 216–218°C. Yield—72%. 1

*thiazolidin-4-one* **(10c)**: mp: 221–223°C Yield—75%. 1

*4-one* **(10d)**: mp: 201–203°C, Yield—85%. <sup>1</sup>

128.5, 125.4, 119.5, 115.4, 85.4, 72.4, 65.9, 63.6, 51.5: MS: m/z (M+

*(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-(4-hydroxyphenyl)thiazolidin-4-one* **(9g)**: mp: 273–275°C,

7.56 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.46 (d, *J* = 8.4 Hz, 2H, Ar-H), 7.32 (d, *J* = 8.6 Hz, 2H, Ar-H), 7.02 (d, *J* = 8.8 Hz, 2H, Ar-H), 5.89–5.80 (m, 2H, 〓CH), 4.96 (d, *J* = 5.4 Hz, 1H, CHS), 4.66 (s, 2H, OCH2), 4.09 (d, *J* = 2H, OCH2), 4.04–3.98 (m, 2H, CH), 3.94 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ170.9, 154.1, 144.4, 134.9, 134.8, 128.8, 127.2,

Calcd for C23H21ClN4O4S: C, 59.96; H, 4.36, N, 11.55; Found: C, 59.38, H, 4.75. N, 11.33. **General procedure for the synthesis of (10a-g)**: A mixture of compound **9a** (0.01 mol), *p*-fluoro benzaldehyde (0.02 mol) and sodium acetate (0.01 mol) in anhydrous glacial acetic acid (20 ml), was refluxed for 3 hours. The reaction mixture was concentrated and then poured into ice cold water, the solid thus separated, was filtered, washed with water and crystallized from glacial acetic acid. To afford

*(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-phenylthiazolidin-4-one*

Ar-H), 7.80 (s, 1H, CH〓C), 7.72 (d, *J* = 9.6 Hz, 2H, Ar-H), 7.40 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.45 (d, *J* = 8.9 Hz, 2H, Ar-H), 7.19 (d, *J* = 8.2 Hz, 2H, Ar-H), 7.02–6.80 (m, 5H, Ar-H), 5.80–5.74 (m, 2H, 〓CH), 4.90 (d, *J* = 5.2 Hz, 1H, CH▬S), 4.52 (s, 2H, OCH2), 4.09–3.94 (m, 2H, 2XCH), 3.79 (d, *J* = 6.6 Hz, 2H, OCH2): 13CNMR (75 MHz, CDCl3): δ170.4, 162.1, 144.1, 141.8, 139.8, 134.1, 130.4, 128.2, 125.6, 124.6,

C30H24ClFN4O3S: C, 62.66; H, 4.21, N, 9.74; Found: C, 62. 48, H, 4.15. N, 9.56. *(R,Z)-3-(4-chlorophenyl)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3 triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)*

8.09 (s, 1H, Ar-H), 7.75 (s, 1H, CH〓C), 7.62 (d, *J* = 9.5 Hz, 2H, Ar-H), 7.52 (d, *J* = 9.4 Hz, 4H, Ar-H), 7.40 (d, *J* = 8.6 Hz, 4H, Ar-H), 7.19 (d, *J* = 8.1 Hz, 2H, Ar-H), 5.84–5.75 (m, 2H, 〓CH), 4.94 (d, *J* = 5.2 Hz, 1H, CH-S), 4.52 (s, 2H, OCH2), 4.06– 3.94 (m, 2H, 2XCH), 3.80 (t, 2H, OCH2): 13CNMR (75 MHz, CDCl3): δ170.5, 162.1, 144.2, 139.2, 134.2, 130.4, 129.2, 125.5, 124.1, 122.2, 119.4, 85.4, 72.8, 65.4, 63.4, 51.2:

*(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-*

δ8.29 (d, *J* = 8.7 Hz, 2H, Ar-H), 8.09 (s, 1H, Ar-H), 7.69 (d, *J* = 9.1 Hz, 2H, Ar-H), 7.65 (s, 1H, CH〓C), 7.61 (d, *J* = 9.4 Hz, 2H, Ar-H), 7.46 (d, *J* = 8.5 Hz, 2H, Ar-H), 7.18 (d, *J* = 8.3 Hz, 2H, Ar-H), 6.84 (d, *J* = 9.8 Hz, 2H, Ar-H), 5.86–5.79 (m, 2H, 〓CH), 4.96 (d, *J* = 5.2 Hz, CH-S), 4.55 (s, 2H, OCH2), 4.05–3.95 (m, 2H, 2XCH), 3.85 (d, *J* = 6.9 Hz, 2H, OCH2): 13CNMR (75 MHz, CDCl3): δ171.5, 162.1, 144.0, 141.8, 134.2, 130.4,

*(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-o-tolylthiazolidin-*

1H, Ar-H), 7.69 (d, *J* = 8.5 Hz, 2H, Ar-H), 7.62 (s, 1H, CH〓C), 7.56 (d, *J* = 9.2 Hz,

(d, *J* = 9.1 Hz, 2H, Ar-H), 5.76 (m, 2H, 〓CH), 4.93 (d, *J* = 5.2 Hz, 1H, CHS), 4.60 (s, 2H, OCH2), 4.05–3.96 (m, 2H, CH), 3.90 (t, 2H, OCH2), 2.1 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.8, 162.9, 144.6, 137.2, 133.2, 130.6, 130.4, 128.2,

*3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-(4-nitrophenyl)*

C30H23ClFN5O5S: C, 58.11; H, 3.74, N, 11.29; Found: C, 57.98, H, 3.55. N, 11.09.

2H, Ar-H), 7.49 (d, *J* = 8.7 Hz, 2H, Ar-H), 7.45–7.39 (m, 4H, Ar-H), 7.10

+Na)632. Anal. Calcd for C30H23Cl2 FN4O3S: C, 59.12; H, 3.80, N, 9.19;

HNMR (300 MHz, CDCl3): δ8.07 (s, 1H,

125.6, 123.2, 119.4, 116.4, 85.4, 72.6, 66.5, 64.0, 51.6, 34.5: MS: m/z (M+

H-NMR (300 MHz, CDCl3): δ9.42 (brs, 1H, Ph-OH), 8.05 (s, 1H, Ar-H),

+H) 485. Anal.

+H) 575. Anal. Calcd for

HNMR (300 MHz, CDCl3):

HNMR (300 MHz, CDCl3):

HNMR (300 MHz, CDCl3): δ8.08 (s,

+H) 620. Calcd for

**124**

MS:m/z(M+

Found: C, 59.01, H, 3.45. N, 8.96.

125.9, 122.7, 119.2, 116.2, 115.4, 84.4, 72.1, 65.3, 63.1, 52.5, 32.0, 17.5: MS: m/z (M<sup>+</sup> +H) 589. Anal. Calcd for C31H26ClFN4O3S: C, 63.21; H, 4.45, N, 9.51; Found: C, 62.75, H, 4.25. N, 9.29.

*(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-p-tolylthiazolidin-4-one* **(10e)**: mp: 205–215°C, Yield—66%. 1 HNMR (300 MHz, CDCl3): δ8.02 (s, 1H, Ar-H), 7.69 (s, 1H, CH〓C), 7.65 (d, *J* = 9.1 Hz, 2H, Ar-H), 7.54 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.42 (d, *J* = 8.7 Hz, 2H, Ar-H), 7.35 (d, *J* = 8.2 Hz, 2H, Ar-H), 7.18 (d, *J* = 8.8 Hz, 2H, Ar-H), 6.80 (d, *J* = 9.4 Hz, 2H, Ar-H), 5.70–5.69 (m, 2H, 〓CH), 4.94 (s, 1H, CHS), 4.55 (s, 2H, OCH2), 4.04–3.98 (m, 2H, CH), 3.96 (t, 2H, OCH2), 2.32 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.1, 162.5, 144.1, 139.5, 137.6, 135.2, 133.2, 130.4, 129.1, 127.5, 124.1, 122.5, 119.5, 115.3, 85.1, 72.5, 66.1, 63.2, 51.2, 21.6: MS: m/z (M+ +H) 589. Anal. Calcd for C31H26ClFN4O3S: C, 63.21; H, 4.45, N, 9.51; Found: C, 62.98, H, 4.25. N, 9.33.

*(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6 dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-(3-hydroxyphenyl)thiazolidin-4-one* **(10f)**: mp: 218–219°C, Yield—82%. 1 H-NMR (300 MHz, CDCl3): δ9.42 (brs, 1H, Ph-OH), 8.08 (s, 1H, Ar-H), 7.71 (d, *J* = 9.7 Hz, 2H, Ar-H), 7.65 (s, 1H, CH〓C), 7.59 (d, *J* = 9.3 Hz, 2H, Ar-H), 7.44 (d, *J* = 8.6 Hz, 2H, Ar-H), 7.15 (d, *J* = 8.4 Hz, 2H, Ar -H), 6.80–6.78 (m, 4H, Ar-H), 5.70–5.68 (m, 2H, 〓CH), 4.92 (d, *J* = 5.2 Hz, 1H, CHS), 4.64 (s, 2H, OCH2), 4.10 (t, 2H, OCH2), 4.01–3.98 (m, 2H, CH): 13CNMR (75 MHz, CDCl3): δ170.5, 162.1, 158.2, 143.8, 139.8, 134.5, 130.8, 128.6, 125.6, 124.1, 122.4, 119.5, 115.7, 114.8, 106.5, 85.4, 72.5, 66.4, 63.4, 51.5: MS: m/z (M+ +H) 591. Anal. Calcd for C30H24ClFN4O4S: C, 60.96; H, 4.09, N, 9.48; Found: C, 60.58, H, 3.85. N, 9.13.

*(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-(4-hydroxyphenyl) thiazolidin-4-one* **(10g)**: mp: 283–285°C, Yield—62%. 1 H-NMR (300 MHz,CDCl3): δ9.42 (brs, 1H, Ph-OH), 8.05 (s, 1H, Ar-H), 7.85 (d, *J* = 9.3 Hz, 2H, Ar-H), 7.65 (s, 1H, CH〓C), 7.56 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.46 (d, *J* = 8.4 Hz, 2H, Ar-H), 7.32 (d, *J* = 8.6 Hz, 2H, Ar-H), 7.19 (d, *J* = 8.3 Hz, 2H, ArH), 7.02 (d, *J* = 8.8 Hz, 2H, Ar-H), 5.89–5.80 (m, 2H, 〓CH), 4.96 (d, *J* = 5.4 Hz, 1H, CHS), 4.66 (s, 2H, OCH2), 4.09 (d, *J* = 2H, OCH2), 4.04–3.98 (m, 2H, CH), 13CNMR (75 MHz, CDCl3): δ170.9, 162.5, 154.1, 144.4, 139.8, 134.9, 134.8, 130.4, 128.8, 127.2, 125.6, 123.2, 119.4, 116.4, 115.9, 85.4, 72.6, 66.5, 64.0, 51.6: MS: m/z (M<sup>+</sup> +H) 591. Anal. Calcd for C30H24ClFN4O4S: C, 60.96; H, 4.09, N, 9.48; Found: C, 60.58, H, 3.95. N, 9.23.

**General procedure for the synthesis of Pyrazole phosphonates (11a-g)**: To a stirred mixture of **10a** (1 mmol), and Bestmann-Ohira Reagent (2.5 mmol) in dry EtOH (10 ml) was added KOH (2.5 mmol) at room temperature, after 2 minutes and irradiated in microwave bath reactor at 500 W for 4–7 minutes at 50°C. The crude product thus obtained was purified by column chromatography on silica gel (60–120 mesh) with hexane-ethyl acetate as eluent. Under conventional method the reaction mixture in EtOH (10 ml) was stirred at room temperature for the appropriate time (**Table 2**).

*Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-8-phenyl-6-thia-1,2,8 triazaspiro[4.4]non-2-en-3-ylphosphonate* **(11a)**: 245–247°C, Yield—75%. 1 HNMR (300 MHz, CDCl3): δ13.06 (brs, 1H, 〓NH), 8.03 (s, 1H, Ar-H), 7.70 (d, *J* = 9.6 Hz, 2H, Ar-H), 7.30 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.45 (d, *J* = 8.9 Hz, 2H, Ar-H), 7.19 (d, *J* = 8.2 Hz, 2H, Ar-H), 6.95–6.70 (m, 5H, Ar-H), 5.80–5.74 (m, 2H, 〓CH), 4.80 (d, *J* = 5.2 Hz, 1H, CH-S), 4.42 (s, 2H, OCH2), 4.09–3.94 (m, 2H, 2XCH), 3.78 (s, 6H, OCH3), 3.69 (d, *J* = 6.6 Hz, 2H, OCH2), 3.52 (s, 1H, CH): 13CNMR (75 MHz, CDCl3): δ170.1, 160.1, 155.2, 144.1, 141.6, 136.2, 134.1, 129.2, 127.5, 125.6, 122.1, 119.1, 115.8, 86.6, 72.9, 63.8, 53.8, 44.5, 34.9: MS: m/z (M+ +H) 725. Anal. Calcd for C33H31ClFN6O6PS: C, 54.66; H, 4.31, N, 11.59; Found: C, 54.48, H, 4.05. N, 11.36.


#### **Table 2.**

*Synthesis of phosphonyl pyrazoles 11(a–g).*

*Dimethyl8-(4-chlorophenyl)-7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3 triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate* **(11b)**: mp: 206–208°C, Yield—82%. <sup>1</sup> HNMR (300 MHz, CDCl3): δ13.11 (brs, 1H, ▬NH), 8.19 (s, 1H, Ar-H), 7.60 (d, *J* = 9.5 Hz, 2H, Ar-H), 7.54 (d, *J* = 9.4 Hz, 4H, Ar-H), 7.30 (d, *J* = 8.6 Hz, 4H, Ar-H), 7.22 (d, *J* = 8.1 Hz, 2H, Ar-H), 5.80–5.78 (m, 2H, 〓CH), 4.92 (d, *J* = 5.2 Hz, 1H, CH-S), 4.52 (s, 2H, OCH2), 4.06–3.94 (m, 2H, 2XCH), 3.80 (t, 2H, OCH2), 3.68 (s, 6H, OCH3), 3.54 (s, 1H, CH): 13CNMR (75 MHz, CDCl3): δ170.9, 162.1, 155.4, 144.2, 139.8, 134.6, 129.5, 125.8, 124.1, 122.0, 119.2, 115.4, 86.1, 72.5, 64.4, 53.5, 44.8, 34.9: MS: m/z (M<sup>+</sup> +Na) 781. Anal. Calcd for C33H30Cl2 FN6O6PS: C, 52.18; H, 3.98, N, 11.06; Found: C, 51.91, H, 3.65. N, 10.86.

*Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-8-(4-nitrophenyl)-9-oxo-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate* **(11c)**: mp: 231–233°C, Yield—82%. 1 HNMR (300 MHz, CDCl3): δ13.06 (brs, 1H, ▬NH), 8.23 (d, *J* = 8.7 Hz, 2H, Ar-H), 8.06 (s, 1H, Ar-H), 7.65 (d, *J* = 9.1 Hz, 2H, Ar-H), 7.51 (d, *J* = 9.4 Hz, 2H, Ar-H), 7.41 (d, *J* = 8.5 Hz, 2H, Ar-H), 7.10 (d, *J* = 8.3 Hz, 2H, Ar-H), 6.64 (d, *J* = 9.8 Hz, 2H, Ar-H), 5.76–5.59 (m, 2H, 〓CH), 4.86 (d, *J* = 5.2 Hz, 1H, CH-S), 4.35 (s, 2H, OCH2), 4.01–3.93 (m, 2H, 2XCH), 3.72 (s, 6H, OCH3), 3.65 (d, *J* = 6.9 Hz, 2H, OCH2), 3.45 (s, 1H, CH), 13CNMR (75 MHz, CDCl3): δ171.1, 162.1, 150.0, 147.8, 144.0, 136.8, 131.4, 128.8, 127.2, 122.0, 119.5, 115.4, 86.4, 72.4, 65.9, 63.9, 53.5, 44.5, 34.8: MS: m/z (M+ +H) 780. Calcd for C33H30ClFN7O8PS: C, 51.47; H, 3.93, N, 12.73; Found: C, 51.18, H, 3.55. N, 12.49.

*Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-8-o-tolyl-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate* **(11d)**: mp: 221–223°C, Yield—75%. 1 HNMR (300 MHz, CDCl3): δ13.10 (brs, 1H, ▬NH), 8.02 (s, 1H, Ar-H), 7.59 (d, *J* = 8.5 Hz, 2H, Ar-H), 7.59 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.44 (d, *J* = 8.7 Hz, 2H, Ar-H), 7.42–7.40 (m, 4H, Ar-H), 7.12 (d, *J* = 9.1 Hz, 2H, Ar-H), 5.76 (m, 2H, 〓CH), 4.92 (d, *J* = 5.2 Hz, 1H, CHS), 4.62 (s, 2H, OCH2), 4.09–3.99 (m, 2H, CH), 3.74 (s, 6H, OCH3), 3.62 (s, 1H, CH), 3.80 (t, 2H, OCH2), 2.12 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.4, 160.1, 155.1, 144.4, 138.6, 136.2, 134.3, 130.7, 128.6, 127.2, 122.0, 119.2, 116.9, 115.4, 86.1, 72.8, 63.8, 53.5, 44.9, 34.8, 17.9: MS: m/z (M+ +H) 739. Anal. Calcd for C34H33ClFN6O6S: C, 55.25; H, 4.50, N, 11.37; Found: C, 55.01, H, 4.25. N, 11.09.

**127**

*Synthesis and Biological Evaluation of Novel Phosphonyl Thiazolo Pyrazoles*

C, 55.25; H, 4.50, N, 11.37; Found: C, 54.98, H, 4.25. N, 11.03.

H, 4.22, N, 11.34; Found: C, 53.18, H, 4.01. N, 11.13.

116.1, 86.4, 73.6, 66.5, 64.0, 53.6, 44.8, 34.9: MS: m/z (M+

Hanamkonda, for his consistent encouragement.

*Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-8-p-tolyl-6-thia-1,2,8 triazaspiro[4.4]non-2-en-3-ylphosphonate* **(11e)**: mp: 209–211°C, Yield—76%.

HNMR (300 MHz, CDCl3): δ13.01 (brs, 1H, ▬NH), 8.07 (s, 1H, Ar-H), 7.62 (d, *J* = 9.1 Hz, 2H, Ar-H), 7.50 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.40 (d, *J* = 8.7 Hz, 2H, Ar-H), 7.32 (d, *J* = 8.2 Hz, 2H, Ar-H), 7.18 (d, *J* = 8.8 Hz, 2H, Ar-H), 6.70

(d, *J* = 9.4 Hz, 2H, Ar-H), 5.60–5.59 (m, 2H, 〓CH), 4.90 (s, 1H, CHS), 4.45 (s, 2H, OCH2), 4.01–3.99 (m, 2H, CH), 3.94 (t, 2H, OCH2), 3.75 (s, 6H, OCH3), 3.62 (s, 1H, CH), 2.30 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.9, 160.1, 155.0, 144.1, 138.7, 136.8, 133.4, 130.4, 129.1, 127.2, 122.0, 119.1, 115.3, 86.1, 72.9, 68.1, 63.9,

*Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-8-(3-hydroxyphenyl)-9-oxo-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate* **(11f )**: mp: 228–229°C,

H-NMR (300 MHz, CDCl3): δ13.09 (brs, 1H, ▬NH), 9.40

*Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-8-(4-hydroxyphenyl)-9-oxo-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate* **(11g)**: mp: 293–295°C,

H-NMR (300 MHz, CDCl3): δ12.85 (brs, 1H, ▬NH), 9.32

(d, *J* = 9.2 Hz, 2H, Ar-H), 7.49 (d, *J* = 8.4 Hz, 2H, Ar-H), 7.30 (d, *J* = 8.6 Hz, 2H, Ar-H), 7.16 (d, *J* = 8.3 Hz, 2H, ArH), 7.0 (d, *J* = 8.8 Hz, 2H, Ar-H), 5.89–5.82 (m, 2H, 〓CH), 4.96 (d, *J* = 5.4 Hz, 1H, CHS), 4.56 (s, 2H, OCH2), 4.07 (d, *J* = 2H, OCH2), 4.02–3.99 (m, 2H, CH), 3.82 (s, 6H, OCH3), 3.62 (s, 1H, CH), 13CNMR (75 MHz, CDCl3): δ172.9, 160.5, 154.3, 144.6, 136.2, 134.9, 134.3, 130.4, 129.8, 127.2, 125.6, 123.2, 119.8,

(brs, 1H, Ph-OH), 8.02 (s, 1H, Ar-H), 7.65 (d, *J* = 9.3 Hz, 2H, Ar-H), 7.59

C33H31ClFN6O7PS: C, 53.48; H, 4.22, N, 11.34; Found: C, 53.18, H, 3.99. N, 11.13.

In conclusion, a series of a new class of hybrid heterocyclic's **11a–g** has been synthesized. The nematicidal activity of these compounds was evaluated against *Dietylenchus myceliophagus* and *Caenorhabditis elegans*. Among synthesized compounds **11b**, **11c**, **11f** and **11g** are the most effective against *Dietylenchus myceliophagus* and *Caenorhabditis elegans* the other test compounds showed moderate activity.

The authors are thankful to CSIR-New Delhi for the financial support (Project

funding no.: 02 (247)15/EMR-II), Director, CSIR-IICT, Hyderabad, India, for NMR and MS spectral analysis and Principal, Vaagdevi Degree and PG College,

+H) 741. Anal. Calcd for C33H31ClFN6O7PS: C, 53.48;

+Na) 763. Anal. Calcd for

(brs, 1H, Ph-OH), 8.04 (s, 1H, Ar-H), 7.61 (d, *J* = 9.7 Hz, 2H, Ar-H), 7.52 (d, *J* = 9.3 Hz, 2H, Ar-H), 7.42 (d, *J* = 8.6 Hz, 2H, Ar-H), 7.13 (d, *J* = 8.4 Hz, 2H, Ar-H), 6.70–6.68 (m, 4H, Ar-H), 5.73–5.70 (m, 2H, =CH), 4.82 (d, *J* = 5.2 Hz, 1H, CHS), 4.54 (s, 2H, OCH2), 4.14 (t, 2H, OCH2), 4.0–3.97 (m, 2H, CH), 3.70 (s, 6H, OCH3), 3.57 (s, 1H, CH): 13CNMR (75 MHz, CDCl3): δ170.2, 156.1, 155.2, 144.8, 136.8, 129.6, 128.2, 127.5, 122.4, 119.4, 115.4, 106.5, 86.4, 72.5, 66.4, 63.4, 53.5,

+H) 739. Anal. Calcd for C31H26ClFN4O3S:

*DOI: http://dx.doi.org/10.5772/intechopen.86977*

53.5, 44.5, 34.8, 21.6: MS: m/z (M+

Yield—88%. 1

Yield—69%. 1

**5. Conclusion**

**Acknowledgements**

44.9, 34.3: MS: m/z (M+

1

*Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-8-p-tolyl-6-thia-1,2,8 triazaspiro[4.4]non-2-en-3-ylphosphonate* **(11e)**: mp: 209–211°C, Yield—76%. 1 HNMR (300 MHz, CDCl3): δ13.01 (brs, 1H, ▬NH), 8.07 (s, 1H, Ar-H), 7.62 (d, *J* = 9.1 Hz, 2H, Ar-H), 7.50 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.40 (d, *J* = 8.7 Hz, 2H, Ar-H), 7.32 (d, *J* = 8.2 Hz, 2H, Ar-H), 7.18 (d, *J* = 8.8 Hz, 2H, Ar-H), 6.70 (d, *J* = 9.4 Hz, 2H, Ar-H), 5.60–5.59 (m, 2H, 〓CH), 4.90 (s, 1H, CHS), 4.45 (s, 2H, OCH2), 4.01–3.99 (m, 2H, CH), 3.94 (t, 2H, OCH2), 3.75 (s, 6H, OCH3), 3.62 (s, 1H, CH), 2.30 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.9, 160.1, 155.0, 144.1, 138.7, 136.8, 133.4, 130.4, 129.1, 127.2, 122.0, 119.1, 115.3, 86.1, 72.9, 68.1, 63.9, 53.5, 44.5, 34.8, 21.6: MS: m/z (M+ +H) 739. Anal. Calcd for C31H26ClFN4O3S: C, 55.25; H, 4.50, N, 11.37; Found: C, 54.98, H, 4.25. N, 11.03.

*Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-8-(3-hydroxyphenyl)-9-oxo-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate* **(11f )**: mp: 228–229°C, Yield—88%. 1 H-NMR (300 MHz, CDCl3): δ13.09 (brs, 1H, ▬NH), 9.40 (brs, 1H, Ph-OH), 8.04 (s, 1H, Ar-H), 7.61 (d, *J* = 9.7 Hz, 2H, Ar-H), 7.52 (d, *J* = 9.3 Hz, 2H, Ar-H), 7.42 (d, *J* = 8.6 Hz, 2H, Ar-H), 7.13 (d, *J* = 8.4 Hz, 2H, Ar-H), 6.70–6.68 (m, 4H, Ar-H), 5.73–5.70 (m, 2H, =CH), 4.82 (d, *J* = 5.2 Hz, 1H, CHS), 4.54 (s, 2H, OCH2), 4.14 (t, 2H, OCH2), 4.0–3.97 (m, 2H, CH), 3.70 (s, 6H, OCH3), 3.57 (s, 1H, CH): 13CNMR (75 MHz, CDCl3): δ170.2, 156.1, 155.2, 144.8, 136.8, 129.6, 128.2, 127.5, 122.4, 119.4, 115.4, 106.5, 86.4, 72.5, 66.4, 63.4, 53.5, 44.9, 34.3: MS: m/z (M+ +H) 741. Anal. Calcd for C33H31ClFN6O7PS: C, 53.48; H, 4.22, N, 11.34; Found: C, 53.18, H, 4.01. N, 11.13.

*Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-8-(4-hydroxyphenyl)-9-oxo-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate* **(11g)**: mp: 293–295°C, Yield—69%. 1 H-NMR (300 MHz, CDCl3): δ12.85 (brs, 1H, ▬NH), 9.32 (brs, 1H, Ph-OH), 8.02 (s, 1H, Ar-H), 7.65 (d, *J* = 9.3 Hz, 2H, Ar-H), 7.59 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.49 (d, *J* = 8.4 Hz, 2H, Ar-H), 7.30 (d, *J* = 8.6 Hz, 2H, Ar-H), 7.16 (d, *J* = 8.3 Hz, 2H, ArH), 7.0 (d, *J* = 8.8 Hz, 2H, Ar-H), 5.89–5.82 (m, 2H, 〓CH), 4.96 (d, *J* = 5.4 Hz, 1H, CHS), 4.56 (s, 2H, OCH2), 4.07 (d, *J* = 2H, OCH2), 4.02–3.99 (m, 2H, CH), 3.82 (s, 6H, OCH3), 3.62 (s, 1H, CH), 13CNMR (75 MHz, CDCl3): δ172.9, 160.5, 154.3, 144.6, 136.2, 134.9, 134.3, 130.4, 129.8, 127.2, 125.6, 123.2, 119.8, 116.1, 86.4, 73.6, 66.5, 64.0, 53.6, 44.8, 34.9: MS: m/z (M+ +Na) 763. Anal. Calcd for C33H31ClFN6O7PS: C, 53.48; H, 4.22, N, 11.34; Found: C, 53.18, H, 3.99. N, 11.13.

#### **5. Conclusion**

*Heterocycles - Synthesis and Biological Activities*

*Dimethyl8-(4-chlorophenyl)-7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3 triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate* **(11b)**: mp: 206–208°C,

**Compound R Mol. formula Reaction time Yield %**

**11a** C6H5 C33H31ClFN6O6PS 3.5 6 62 89 **11b** 4-Cl-C6H4 C33H30Cl2FN6O6PS 2.5 4 60 85 **11c** 4-NO2-C6H4 C33H30ClFN7O8PS 2.0 5 61 84 **11d** 2-CH3-C6H4 C34H33ClFN6O6PS 3.0 6 65 86 **11e** 4-CH3-C6H4 C34H33ClFN6O6PS 3.2 4 69 85 **11f** 3-OH-C6H4 C35H31ClFN6O7PS 2.0 5 72 89 **11g** 4-OH-C6H4 C35H35ClFN6O7PS 3.0 4 71 82

**A (hours)**

**B (minutes)** **A B**

HNMR (300 MHz, CDCl3): δ13.11 (brs, 1H, ▬NH), 8.19 (s, 1H, Ar-H), 7.60 (d, *J* = 9.5 Hz, 2H, Ar-H), 7.54 (d, *J* = 9.4 Hz, 4H, Ar-H), 7.30 (d, *J* = 8.6 Hz, 4H, Ar-H), 7.22 (d, *J* = 8.1 Hz, 2H, Ar-H), 5.80–5.78 (m, 2H, 〓CH), 4.92 (d, *J* = 5.2 Hz, 1H, CH-S), 4.52 (s, 2H, OCH2), 4.06–3.94 (m, 2H, 2XCH), 3.80 (t, 2H, OCH2), 3.68 (s, 6H, OCH3), 3.54 (s, 1H, CH): 13CNMR (75 MHz, CDCl3): δ170.9, 162.1, 155.4, 144.2, 139.8, 134.6, 129.5, 125.8, 124.1, 122.0, 119.2, 115.4,

*Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-8-(4-nitrophenyl)-9-oxo-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate* **(11c)**: mp: 231–233°C, Yield—82%.

HNMR (300 MHz, CDCl3): δ13.06 (brs, 1H, ▬NH), 8.23 (d, *J* = 8.7 Hz, 2H, Ar-H), 8.06 (s, 1H, Ar-H), 7.65 (d, *J* = 9.1 Hz, 2H, Ar-H), 7.51 (d, *J* = 9.4 Hz, 2H, Ar-H), 7.41 (d, *J* = 8.5 Hz, 2H, Ar-H), 7.10 (d, *J* = 8.3 Hz, 2H, Ar-H), 6.64 (d, *J* = 9.8 Hz, 2H, Ar-H), 5.76–5.59 (m, 2H, 〓CH), 4.86 (d, *J* = 5.2 Hz, 1H, CH-S), 4.35 (s, 2H, OCH2), 4.01–3.93 (m, 2H, 2XCH), 3.72 (s, 6H, OCH3), 3.65 (d, *J* = 6.9 Hz, 2H, OCH2), 3.45 (s, 1H, CH), 13CNMR (75 MHz, CDCl3): δ171.1, 162.1, 150.0, 147.8, 144.0, 136.8, 131.4, 128.8, 127.2,

for C33H30ClFN7O8PS: C, 51.47; H, 3.93, N, 12.73; Found: C, 51.18, H, 3.55. N, 12.49. *Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- 3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-8-o-tolyl-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate* **(11d)**: mp: 221–223°C, Yield—75%. 1

Ar-H), 7.59 (d, *J* = 9.2 Hz, 2H, Ar-H), 7.44 (d, *J* = 8.7 Hz, 2H, Ar-H), 7.42–7.40

(300 MHz, CDCl3): δ13.10 (brs, 1H, ▬NH), 8.02 (s, 1H, Ar-H), 7.59 (d, *J* = 8.5 Hz, 2H,

(m, 4H, Ar-H), 7.12 (d, *J* = 9.1 Hz, 2H, Ar-H), 5.76 (m, 2H, 〓CH), 4.92 (d, *J* = 5.2 Hz, 1H, CHS), 4.62 (s, 2H, OCH2), 4.09–3.99 (m, 2H, CH), 3.74 (s, 6H, OCH3), 3.62 (s, 1H, CH), 3.80 (t, 2H, OCH2), 2.12 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.4, 160.1, 155.1, 144.4, 138.6, 136.2, 134.3, 130.7, 128.6, 127.2, 122.0, 119.2, 116.9, 115.4, 86.1,

FN6O6PS: C, 52.18; H, 3.98, N, 11.06; Found: C, 51.91, H, 3.65. N, 10.86.

122.0, 119.5, 115.4, 86.4, 72.4, 65.9, 63.9, 53.5, 44.5, 34.8: MS: m/z (M+

+Na) 781. Anal. Calcd for C33H30Cl2

+H) 739. Anal. Calcd for C34H33ClFN6O6S:

+H) 780. Calcd

HNMR

**126**

Yield—82%. <sup>1</sup>

**Table 2.**

1

86.1, 72.5, 64.4, 53.5, 44.8, 34.9: MS: m/z (M<sup>+</sup>

*A: conventional method; B: microwave irradiation method.*

*Synthesis of phosphonyl pyrazoles 11(a–g).*

72.8, 63.8, 53.5, 44.9, 34.8, 17.9: MS: m/z (M+

C, 55.25; H, 4.50, N, 11.37; Found: C, 55.01, H, 4.25. N, 11.09.

In conclusion, a series of a new class of hybrid heterocyclic's **11a–g** has been synthesized. The nematicidal activity of these compounds was evaluated against *Dietylenchus myceliophagus* and *Caenorhabditis elegans*. Among synthesized compounds **11b**, **11c**, **11f** and **11g** are the most effective against *Dietylenchus myceliophagus* and *Caenorhabditis elegans* the other test compounds showed moderate activity.

#### **Acknowledgements**

The authors are thankful to CSIR-New Delhi for the financial support (Project funding no.: 02 (247)15/EMR-II), Director, CSIR-IICT, Hyderabad, India, for NMR and MS spectral analysis and Principal, Vaagdevi Degree and PG College, Hanamkonda, for his consistent encouragement.

*Heterocycles - Synthesis and Biological Activities*

#### **Author details**

Avula Srinivas Department of Chemistry, Vaagdevi Degree and PG College Kishanpura, Warangal, Telangana, India

\*Address all correspondence to: avula.sathwikreddy@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.

**129**

*Synthesis and Biological Evaluation of Novel Phosphonyl Thiazolo Pyrazoles*

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**128**

**Author details**

Avula Srinivas

Telangana, India

Department of Chemistry, Vaagdevi Degree and PG College Kishanpura, Warangal,

© 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: avula.sathwikreddy@gmail.com

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[57] Noling JW, Becker JO. The challenge of research and extension to define and implement alternatives to methyl bromide. Journal of Nematology. 1994;**26**:573

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[59] Yuji O, Sengual N, Eli P, Uzi R, Zohara Y, Yitzhak S. Nematicidal activity of essential oils and their components against the rootknot nematode. Phytopathology. 2000;**90**:710

[60] Srinivas A, Sunitha M, Karthik P, Nikitha G, Raju K, Ravinder B, et al. Synthesis, nematicidal and antifungal properties of hybrid heterocyclics. Journal of Heterocyclic Chemistry. 2017;**54**:3250

[61] Srinivas A, Santhosh M, Sunitha M, Karthik P, Srinivas K, Vasumathi Reddy K. Synthesis and biological evaluation of triazole linked thiazolidenone glycosides. Acta Chimica Slovenica. 2016;**63**:827

[62] Srinivas A. Synthesis and Antimicrobial Activity of Bis[4 methoxy-3-(6-aryl-7H-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazin-3-yl)phenyl]methanesand Bis[(triazolo[3,4-b]thiadiazepin-3-yl) phenyl]methanes. Acta Chimica Slovenica. 2016;**63**:344

[63] Srinivas A, Sunitha M. Synthesis of piparonyl triazoles as anti microbial agents. Indian Journal of Chemistry, Section A. 2016;**55B**:102

[64] Srinivas A, Sunitha M. Synthesis of 1,2,3-triazole glycosides as anticancer agents. Indian Journal of Chemistry Section B. 2016;**55B**:231

[65] Reddy CS, Srinivas A, Sunitha M, Nagaraj A. Design and synthesis of novel methylene-bis-fused pyrazoles as biologically active molecules. Journal of Heterocyclic Chemistry. 2010;**47**:1303

[66] Srinivas A, Reddy CS, Nagaraj A. Synthesis, Nematicidal and Antimicrobial Properties of Bis-[4-methoxy-3-[3-(4 fluorophenyl)-6-(4-methylphenyl)- 2(aryl)-tetrahydro-2Hpyrazolo[3,4-d] thiazol-5-yl]phenyl]methanes. Chemical & Pharmaceutical Bulletin. 2009;**57**:685

[67] Reddy CS, Srinivas A, Nagaraj A. Synthesis and in vitro study of a new class of methylenebis-4,6 diarylbenzo[d]isoxazoles as potential antifungal agents. Journal of Heterocyclic Chemistry. 2009;**46**:497

[68] Reddy CS, Srinivas A, Nagaraj A. Synthesis of some novel methylene-bispyrimidinyl-spiro-4-thiazolidinones as biologically potent agents. Journal of Heterocyclic Chemistry. 2008;**45**:1121

[69] Srinivas A, Nagaraj A, Sanjeeva Reddy CH. Synthesis and biological evaluation of novel methylenebisthiazolidinone derivatives as potential nematicidal agents. Journal of Heterocyclic Chemistry. 2008;**45**:999

[70] McBeth CW, Bergerson GB. Nematicidal activity of heterocyclics. Phytopathology. 1953;**43**:264

**133**

activities.

**Chapter 10**

**Abstract**

and Bioactivity

*Yamajala B.R.D. Rajesh*

and miscellaneous activities.

philic and nucleophilic substitution reactions.

biological activity

**1. Introduction**

Quinoline Heterocycles: Synthesis

Among heterocyclic compounds, quinoline is a privileged scaffold that appears as an important construction motif for the development of new drugs. Quinoline nucleus is endowed with a variety of therapeutic activities, and new quinolone derivatives are known to be biologically active compounds possessing several pharmacological activities. Many new therapeutic agents have been developed by using quinoline nucleus. Hence, quinoline and its derivatives form an important class of heterocyclic compounds for the new drug development. Numerous synthetic routes have been developed for the synthesis of quinoline and its derivatives due to its wide range of biological and pharmacological activities. The article covers the synthesis as well as biological activities of quinoline derivatives such as antimalarial, anticancer, antibacterial, anthelmintic, antiviral, antifungal, antiinflammatory, analgesic, cardiovascular, central nervous system, hypoglycemic,

**Keywords:** quinoline, heterocyclic compound, quinoline derivatives, synthesis,

Quinoline **1** or 1-azanaphthalene or benzo[*b*]pyridine is an aromatic nitrogencontaining heterocyclic compound having a molecular formula of C9H7N, and the molecular weight is 129.16. Being a weak tertiary base, it forms salts with acids and exhibits reactions similar to benzene and pyridine. It participates in both electro-

Quinoline moiety commonly exists in various natural compounds (*Cinchona* alkaloids), and pharmacological studies have shown that the quinolone ring system is present in many compounds exhibiting a broad range of biological activities. Quinoline has been found to have antibacterial, antifungal, antimalarial, anthelmintic, anticonvulsant, cardiotonic, anti-inflammatory, and analgesic

#### **Chapter 10**

*Heterocycles - Synthesis and Biological Activities*

[63] Srinivas A, Sunitha M. Synthesis of piparonyl triazoles as anti microbial agents. Indian Journal of Chemistry,

[64] Srinivas A, Sunitha M. Synthesis of 1,2,3-triazole glycosides as anticancer agents. Indian Journal of Chemistry

[65] Reddy CS, Srinivas A, Sunitha M, Nagaraj A. Design and synthesis of novel methylene-bis-fused pyrazoles as biologically active molecules. Journal of Heterocyclic Chemistry. 2010;**47**:1303

[66] Srinivas A, Reddy CS, Nagaraj A.

fluorophenyl)-6-(4-methylphenyl)- 2(aryl)-tetrahydro-2Hpyrazolo[3,4-d] thiazol-5-yl]phenyl]methanes. Chemical & Pharmaceutical Bulletin.

[67] Reddy CS, Srinivas A, Nagaraj A. Synthesis and in vitro study of a new class of methylenebis-4,6 diarylbenzo[d]isoxazoles as potential

Heterocyclic Chemistry. 2009;**46**:497

[68] Reddy CS, Srinivas A, Nagaraj A. Synthesis of some novel methylene-bispyrimidinyl-spiro-4-thiazolidinones as biologically potent agents. Journal of Heterocyclic Chemistry. 2008;**45**:1121

[69] Srinivas A, Nagaraj A, Sanjeeva Reddy CH. Synthesis and biological evaluation of novel methylenebisthiazolidinone derivatives as

potential nematicidal agents. Journal of Heterocyclic Chemistry. 2008;**45**:999

[70] McBeth CW, Bergerson GB. Nematicidal activity of heterocyclics.

Phytopathology. 1953;**43**:264

antifungal agents. Journal of

Synthesis, Nematicidal and Antimicrobial Properties of Bis-[4-methoxy-3-[3-(4-

2009;**57**:685

Section A. 2016;**55B**:102

Section B. 2016;**55B**:231

[55] Jayasinghe ULB, Kumarihamy BMM, Bandara AGD, Vasquez EA, Karus W. Nematicidal activity of some sri lankan plants. Natural Product

[56] Xaki MH, Moran D, Harries D. Pesticides in groundwater: The aldicarb story in Suffolk County, NY. American Journal of Public Health. 1982;**72**:1391

[57] Noling JW, Becker JO. The challenge of research and extension to define and implement alternatives to methyl bromide. Journal of Nematology.

[58] Kagan J, Kagan PA, Bushe HE. Lightdependent toxicity of α-terthienyl and anthracene toward late embryonic stages of Rana pipiens. Journal of Chemical

[59] Yuji O, Sengual N, Eli P, Uzi R, Zohara Y, Yitzhak S. Nematicidal activity of essential oils and their components against the rootknot nematode. Phytopathology.

[60] Srinivas A, Sunitha M, Karthik P, Nikitha G, Raju K, Ravinder B, et al. Synthesis, nematicidal and antifungal properties of hybrid heterocyclics. Journal of Heterocyclic Chemistry.

[61] Srinivas A, Santhosh M, Sunitha M, Karthik P, Srinivas K, Vasumathi Reddy K. Synthesis and biological evaluation of triazole linked thiazolidenone glycosides. Acta Chimica Slovenica.

[62] Srinivas A. Synthesis and Antimicrobial Activity of Bis[4 methoxy-3-(6-aryl-7H-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazin-3-yl)phenyl]methanesand

Slovenica. 2016;**63**:344

Bis[(triazolo[3,4-b]thiadiazepin-3-yl) phenyl]methanes. Acta Chimica

Research. 2003;**17**:259

1994;**26**:573

2000;**90**:710

2017;**54**:3250

2016;**63**:827

Ecology. 1984;**10**:1115

**132**

## Quinoline Heterocycles: Synthesis and Bioactivity

*Yamajala B.R.D. Rajesh*

#### **Abstract**

Among heterocyclic compounds, quinoline is a privileged scaffold that appears as an important construction motif for the development of new drugs. Quinoline nucleus is endowed with a variety of therapeutic activities, and new quinolone derivatives are known to be biologically active compounds possessing several pharmacological activities. Many new therapeutic agents have been developed by using quinoline nucleus. Hence, quinoline and its derivatives form an important class of heterocyclic compounds for the new drug development. Numerous synthetic routes have been developed for the synthesis of quinoline and its derivatives due to its wide range of biological and pharmacological activities. The article covers the synthesis as well as biological activities of quinoline derivatives such as antimalarial, anticancer, antibacterial, anthelmintic, antiviral, antifungal, antiinflammatory, analgesic, cardiovascular, central nervous system, hypoglycemic, and miscellaneous activities.

**Keywords:** quinoline, heterocyclic compound, quinoline derivatives, synthesis, biological activity

#### **1. Introduction**

Quinoline **1** or 1-azanaphthalene or benzo[*b*]pyridine is an aromatic nitrogencontaining heterocyclic compound having a molecular formula of C9H7N, and the molecular weight is 129.16. Being a weak tertiary base, it forms salts with acids and exhibits reactions similar to benzene and pyridine. It participates in both electrophilic and nucleophilic substitution reactions.

Quinoline moiety commonly exists in various natural compounds (*Cinchona* alkaloids), and pharmacological studies have shown that the quinolone ring system is present in many compounds exhibiting a broad range of biological activities. Quinoline has been found to have antibacterial, antifungal, antimalarial, anthelmintic, anticonvulsant, cardiotonic, anti-inflammatory, and analgesic activities.

#### **2. Synthesis**

In the literature, a number of established protocols have been reported for the synthesis of quinoline ring, which can be altered to produce a number of differently substituted quinolines. The quinoline ring has been generally synthesized by various conventional named reactions such as Skraup, Doebner-Von Miller, Pfitzinger, Friedlander, Conrad-Limpach, and Combes synthesis (**Figure 1**) [1].

**Figure 1.** *Conventional methods of synthesis of various substituted quinolines.*

Apart from the conventional methods, a vast number of synthetic routes have been developed for the synthesis of quinoline and quinoline derivatives. Chen et al. reported the synthesis of 2,4-disubstituted quinolines, **2** by the condensation of 2-iodoanilines with alkynyl aryl ketones using nickel catalyst [2].

2,4-Disubstituted quinolones, **3** have been obtained by the cyclization of 2-aminoaryl ketones with phenylacetylenes. This reaction takes place in ionic liquid medium ([hmim]PF6) in the presence of zinc trifluoromethanesulfonate catalyst [3]. Lekhok et al. synthesized the same product in the presence of catalytic amount of indium(III) trifluoromethanesulfonate (In(CF3SO3)3) under microwave and solvent-free conditions [4].

**135**

*Quinoline Heterocycles: Synthesis and Bioactivity DOI: http://dx.doi.org/10.5772/intechopen.81239*

proceeds with the help of a zeolite catalyst, E4a [5].

poly-substituted quinolones, **6** have been synthesized [7].

Here, benzophenone acts as a hydride scavenger.

proceeded under basic conditions.

tributyltin hydride [10].

2,4-Diphenyl-2-methyl-1,2-dihydroquinoline, **4** has been prepared by the condensation followed by cyclization of aniline and acetophenone. The reaction

2,3,4-Trisubstituted quinolones, **5** have been synthesized by Friedlander annulation of 2-amino substituted aromatic ketones and reactive methylene group containing carbonyl compounds in the presence of ethyl ammonium nitrate (EAN) [6].

By stirring 2-aminoaryl ketones and various α-methylene ketones in the presence of dodecylphosphonic acid (DPA) catalyst in water or solvent-free conditions,

2-Aminobenzyl alcohol reacts with ketones or alcohols in the presence of a base, and benzophenone resulted in the formation of poly-substituted quinolones, **7** [8].

Horn et al. reported the synthesis of quinolines, **8** from α, β-unsaturated ketones and *o*-aminophenylboronic acid derivatives [9]. This method is the modification of the conventional Skraup-Doebner-Von Miller synthesis and that the reaction

3,4-Dihydroquinolin-2-ones, **9** have been synthesized by treating 2-iodoanilines

and various acrylates using azobisisobutyronitrile (AIBN) in the presence of

*Quinoline Heterocycles: Synthesis and Bioactivity DOI: http://dx.doi.org/10.5772/intechopen.81239*

*Heterocycles - Synthesis and Biological Activities*

In the literature, a number of established protocols have been reported for the synthesis of quinoline ring, which can be altered to produce a number of differently substituted quinolines. The quinoline ring has been generally synthesized by various conventional named reactions such as Skraup, Doebner-Von Miller, Pfitzinger,

Apart from the conventional methods, a vast number of synthetic routes have been developed for the synthesis of quinoline and quinoline derivatives. Chen et al. reported the synthesis of 2,4-disubstituted quinolines, **2** by the condensation of

2,4-Disubstituted quinolones, **3** have been obtained by the cyclization of 2-aminoaryl ketones with phenylacetylenes. This reaction takes place in ionic liquid medium ([hmim]PF6) in the presence of zinc trifluoromethanesulfonate catalyst [3]. Lekhok et al. synthesized the same product in the presence of catalytic amount of indium(III) trifluoromethanesulfonate (In(CF3SO3)3) under microwave and

2-iodoanilines with alkynyl aryl ketones using nickel catalyst [2].

*Conventional methods of synthesis of various substituted quinolines.*

Friedlander, Conrad-Limpach, and Combes synthesis (**Figure 1**) [1].

**2. Synthesis**

**134**

**Figure 1.**

solvent-free conditions [4].

2,4-Diphenyl-2-methyl-1,2-dihydroquinoline, **4** has been prepared by the condensation followed by cyclization of aniline and acetophenone. The reaction proceeds with the help of a zeolite catalyst, E4a [5].

2,3,4-Trisubstituted quinolones, **5** have been synthesized by Friedlander annulation of 2-amino substituted aromatic ketones and reactive methylene group containing carbonyl compounds in the presence of ethyl ammonium nitrate (EAN) [6].

By stirring 2-aminoaryl ketones and various α-methylene ketones in the presence of dodecylphosphonic acid (DPA) catalyst in water or solvent-free conditions, poly-substituted quinolones, **6** have been synthesized [7].

2-Aminobenzyl alcohol reacts with ketones or alcohols in the presence of a base, and benzophenone resulted in the formation of poly-substituted quinolones, **7** [8]. Here, benzophenone acts as a hydride scavenger.

Horn et al. reported the synthesis of quinolines, **8** from α, β-unsaturated ketones and *o*-aminophenylboronic acid derivatives [9]. This method is the modification of the conventional Skraup-Doebner-Von Miller synthesis and that the reaction proceeded under basic conditions.

3,4-Dihydroquinolin-2-ones, **9** have been synthesized by treating 2-iodoanilines and various acrylates using azobisisobutyronitrile (AIBN) in the presence of tributyltin hydride [10].

Wang et al. developed a method for the synthesis of 2-phenylquinoline-4-carboxylic acids, **10** by the treatment of pyruvic acid with substituted aniline and benzaldehyde in the presence of rare-earth metal catalysts in water under reflux condition [11].

Kouznetsov et al. synthesized phenyl-substituted quinolones, **11** by reacting ethyl vinyl ether or ethyl vinyl sulfide with N-arylaldimine in the presence of Lewis acidic catalysts such as boron trifluoride etherate (BF3.OEt2) to obtain 2,4-substituted tetrahydroquinolines. The tetrahydroquinolines were aromatized to 2-phenylsubstituted quinolines under vacuum distillation in the presence of *p*-TSOH [12].

Wang et al. reported the synthesis of 2-phenyl-4-alkoxy quinolines, **12** by cyclocondensation of 2-(2-trimethylsilyl)ethynyl) aniline with aromatic aldehydes in the presence of sulfuric acid as catalyst in methanol solvent [13].

Two molecules of *o*-haloacetophenones condensed with urea or primary amines yielded certain halogen-substituted quinolones, **13**. The halogen-substituted quinolines were formed through the cleavage of C(sp2 )–halogen and α-C(sp3 )–H bonds and the formation of new bonds in a selective manner [14].

A one-pot reaction of 2-aminoaryl ketones with certain arylacetylenes results in the formation of 2,4-disubstituted quinolones, **14**. The reaction was performed in a green synthetic route using potassium dodecatugstocobaltate trihydrate (K5CoW12O40.3H2O) as a recyclable and eco-friendly catalyst under microwave and solvent-free conditions [15].

**137**

**3. Biological activity**

**3.1 Antimalarial**

*Quinoline Heterocycles: Synthesis and Bioactivity DOI: http://dx.doi.org/10.5772/intechopen.81239*

group being replaced by oxygen nucleophiles.

Kowsari et al. synthesized certain quinolones, **15** by reacting isatin with aryl methyl ketones in the presence of basic ionic liquids in water [16]. The reaction was conducted under ultrasound green synthetic conditions. The main advantages of this procedure are (i) a green method, (ii) milder and shorter reaction time, and

1,4-Diazabicyclo[2.2.2]octane (DABCO) promoted structurally diverse 2-alkoxy- and 2-aryloxy-3-substituted quinolones, **16** that have been synthesized by treating *o*-alkynylaryl isocyanides with alcohols and phenols [17]. DABCO initiates the reaction as a nucleophile and facilitates the formation of the product as a leaving

Benzimidoyl chlorides when treated with 1-(1-(allyloxy)prop-2-ynyl)benzene (1,6-enynes) yielded diverse quinoline derivatives, **17** via a domino palladium-

Diversified quinolones, **18** have been synthesized by the intramolecular cyclocondensation of 1-azido-2-(2-propynyl)benzenes using electrophilic reagents (I2, Br2, ICl, NBS, NIS, and HNTf2) in nitromethane at 0°C to room temperature. The reaction

Quinolines are known for their excellent antimalarial properties. Raynes et al. developed bisquinolines, **19, 20** that exhibit antimalarial activity against chloroquine-resistant and chloroquine-sensitive parasites [20]. Derivatives of ferrochloroquine, **21** were also found to possess antimalarial activity [21]. In these derivatives, the carbon skeleton of chloroquine is replaced by ferrocene group. Modapa et al.

also proceeds in the presence of AuCl3/AgNTf2 catalysts in THF at 100°C [19].

catalyzed Sonogashira coupling and followed by cyclization [18].

(iii) higher yields and selectivity without a transition metal catalyst.

*Quinoline Heterocycles: Synthesis and Bioactivity DOI: http://dx.doi.org/10.5772/intechopen.81239*

*Heterocycles - Synthesis and Biological Activities*

condition [11].

Wang et al. developed a method for the synthesis of 2-phenylquinoline-4-carboxylic acids, **10** by the treatment of pyruvic acid with substituted aniline and benzaldehyde in the presence of rare-earth metal catalysts in water under reflux

Kouznetsov et al. synthesized phenyl-substituted quinolones, **11** by reacting ethyl vinyl ether or ethyl vinyl sulfide with N-arylaldimine in the presence of Lewis acidic catalysts such as boron trifluoride etherate (BF3.OEt2) to obtain 2,4-substituted tetrahydroquinolines. The tetrahydroquinolines were aromatized to 2-phenylsubstituted quinolines under vacuum distillation in the presence of *p*-TSOH [12].

Wang et al. reported the synthesis of 2-phenyl-4-alkoxy quinolines, **12** by cyclocondensation of 2-(2-trimethylsilyl)ethynyl) aniline with aromatic aldehydes

Two molecules of *o*-haloacetophenones condensed with urea or primary amines

A one-pot reaction of 2-aminoaryl ketones with certain arylacetylenes results in the formation of 2,4-disubstituted quinolones, **14**. The reaction was performed in a

(K5CoW12O40.3H2O) as a recyclable and eco-friendly catalyst under microwave and

)–halogen and α-C(sp3

)–H

yielded certain halogen-substituted quinolones, **13**. The halogen-substituted

in the presence of sulfuric acid as catalyst in methanol solvent [13].

bonds and the formation of new bonds in a selective manner [14].

green synthetic route using potassium dodecatugstocobaltate trihydrate

quinolines were formed through the cleavage of C(sp2

**136**

solvent-free conditions [15].

Kowsari et al. synthesized certain quinolones, **15** by reacting isatin with aryl methyl ketones in the presence of basic ionic liquids in water [16]. The reaction was conducted under ultrasound green synthetic conditions. The main advantages of this procedure are (i) a green method, (ii) milder and shorter reaction time, and (iii) higher yields and selectivity without a transition metal catalyst.

1,4-Diazabicyclo[2.2.2]octane (DABCO) promoted structurally diverse 2-alkoxy- and 2-aryloxy-3-substituted quinolones, **16** that have been synthesized by treating *o*-alkynylaryl isocyanides with alcohols and phenols [17]. DABCO initiates the reaction as a nucleophile and facilitates the formation of the product as a leaving group being replaced by oxygen nucleophiles.

Benzimidoyl chlorides when treated with 1-(1-(allyloxy)prop-2-ynyl)benzene (1,6-enynes) yielded diverse quinoline derivatives, **17** via a domino palladiumcatalyzed Sonogashira coupling and followed by cyclization [18].

Diversified quinolones, **18** have been synthesized by the intramolecular cyclocondensation of 1-azido-2-(2-propynyl)benzenes using electrophilic reagents (I2, Br2, ICl, NBS, NIS, and HNTf2) in nitromethane at 0°C to room temperature. The reaction also proceeds in the presence of AuCl3/AgNTf2 catalysts in THF at 100°C [19].

#### **3. Biological activity**

#### **3.1 Antimalarial**

Quinolines are known for their excellent antimalarial properties. Raynes et al. developed bisquinolines, **19, 20** that exhibit antimalarial activity against chloroquine-resistant and chloroquine-sensitive parasites [20]. Derivatives of ferrochloroquine, **21** were also found to possess antimalarial activity [21]. In these derivatives, the carbon skeleton of chloroquine is replaced by ferrocene group. Modapa et al.

reported that the synthesis of ureido-4-quinolinamides, **22** showed antimalarial activity at MIC 0.25 mg/mL against chloroquine-sensitive *Plasmodium falciparum* strain [22]. Several 7-chloroquinolinyl thioureas, **23, 24** have been synthesized by Mahajan et al. that possess excellent antimalarial properties [23]. Kovi et al. synthesized a chloroquinolyl derivative, **25** that has an excellent antimalarial activity even at very low concentrations [24]. Acharya et al. reported the synthesis and potent antimalarial activity of certain pyridine-quinoline hybrid conjugates, **26, 27** against chloroquine susceptible *P. falciparum* strain [25]. Shiraki et al. produced some 5-aryl-8-aminoquinolines, **28** with good antimalarial activity and had mild hemolytic activity than tafenoquine [26]. Singh et al. developed several antimalarial 4-anilinoquinolines, **29** which showed good antimalarial activity against chloroquine-sensitive *P. falciparum* strains [27]. Novel hybrid conjugates of N-(7 chloroquinolin-4-yl) piperazine-1-carbothioamide and 1,3,5-triazine derivatives, **30** have been synthesized by Bhat et al. These hybrid conjugates possess considerable antimalarial activity against both wild and mutant parasites on changing the pattern of substitution [28]. McNulty et al. developed 4-arylquinoline-2-carboxylate derivatives, **31** which show antiprotozoal activity against the pathogenic parasite *Toxoplasma gondii* [29].

#### **3.2 Anti-inflammatory activity**

A quinoline derivative, **32** with strong anti-inflammatory activity was synthesized by Baba et al. in adjuvant arthritis rat model [30]. Chen et al. developed

**139**

*Quinoline Heterocycles: Synthesis and Bioactivity DOI: http://dx.doi.org/10.5772/intechopen.81239*

**3.3 Analgesic activity**

**3.4 Antibacterial**

amino-acetamide inhibitors of aggrecanase-2 [31].

2-(furan-2-yl)-4-phenoxy-quinoline derivatives, **33, 34** that inhibit the lysozyme and β-glucuronidase release [2]. Few quinoline derivatives, **35, 36** have been synthesized and evaluated by Gilbert et al. for treating osteoarthritis and that are

4-Substituted-7-trifluoromethylquinolines **37, 38** have been developed by Abadi et al., and these derivatives were found to possess excellent analgesic activity with nitric oxide releasing characteristics [32]. Gomtsyan et al. synthesized an analgesic active derivative, **39**. The activity is due to its antagonism at vanilloid receptors [33].

Some quinoline derivatives, **40** were synthesized by Manera et al. that show analgesic activity and are selective agonists at cannabinoid CB2 receptors [34].

Ma et al. reported the synthesis and antibacterial evaluation of phenoxy-, phenylthio-, and benzyloxy-substituted quinolones, **41** [35]. A few 8-substituted quinoline carboxylic acids, **42** were synthesized by Sanchez et al. that showed antibacterial activity [36]. Upadhayaya et al. developed 3-benzyl-6-bromo-2-me-

*Mycobacterium tuberculosis* H37Rv strain [37]. A few analogues of 7-chloro quinolones, **44** were synthesized by De Souza et al., and these derivatives were found to be effective against multidrug-resistant tuberculosis [38]. Lilienkampf et al. synthesized quinoline-based compounds containing an isoxazole unit and side chain, **45** that was active against *Mycobacterium tuberculosis* [39]. The novel hybrid

thoxy quinoline derivatives, **43,** and these derivatives are active against

*Quinoline Heterocycles: Synthesis and Bioactivity DOI: http://dx.doi.org/10.5772/intechopen.81239*

*Heterocycles - Synthesis and Biological Activities*

*Toxoplasma gondii* [29].

reported that the synthesis of ureido-4-quinolinamides, **22** showed antimalarial activity at MIC 0.25 mg/mL against chloroquine-sensitive *Plasmodium falciparum* strain [22]. Several 7-chloroquinolinyl thioureas, **23, 24** have been synthesized by Mahajan et al. that possess excellent antimalarial properties [23]. Kovi et al. synthesized a chloroquinolyl derivative, **25** that has an excellent antimalarial activity even at very low concentrations [24]. Acharya et al. reported the synthesis and potent antimalarial activity of certain pyridine-quinoline hybrid conjugates, **26, 27** against chloroquine susceptible *P. falciparum* strain [25]. Shiraki et al. produced some 5-aryl-8-aminoquinolines, **28** with good antimalarial activity and had mild hemolytic activity than tafenoquine [26]. Singh et al. developed several antimalarial 4-anilinoquinolines, **29** which showed good antimalarial activity against chloroquine-sensitive *P. falciparum* strains [27]. Novel hybrid conjugates of N-(7 chloroquinolin-4-yl) piperazine-1-carbothioamide and 1,3,5-triazine derivatives, **30** have been synthesized by Bhat et al. These hybrid conjugates possess considerable antimalarial activity against both wild and mutant parasites on changing the pattern of substitution [28]. McNulty et al. developed 4-arylquinoline-2-carboxylate derivatives, **31** which show antiprotozoal activity against the pathogenic parasite

**138**

**3.2 Anti-inflammatory activity**

A quinoline derivative, **32** with strong anti-inflammatory activity was synthesized by Baba et al. in adjuvant arthritis rat model [30]. Chen et al. developed 2-(furan-2-yl)-4-phenoxy-quinoline derivatives, **33, 34** that inhibit the lysozyme and β-glucuronidase release [2]. Few quinoline derivatives, **35, 36** have been synthesized and evaluated by Gilbert et al. for treating osteoarthritis and that are amino-acetamide inhibitors of aggrecanase-2 [31].

#### **3.3 Analgesic activity**

4-Substituted-7-trifluoromethylquinolines **37, 38** have been developed by Abadi et al., and these derivatives were found to possess excellent analgesic activity with nitric oxide releasing characteristics [32]. Gomtsyan et al. synthesized an analgesic active derivative, **39**. The activity is due to its antagonism at vanilloid receptors [33]. Some quinoline derivatives, **40** were synthesized by Manera et al. that show analgesic activity and are selective agonists at cannabinoid CB2 receptors [34].

#### **3.4 Antibacterial**

Ma et al. reported the synthesis and antibacterial evaluation of phenoxy-, phenylthio-, and benzyloxy-substituted quinolones, **41** [35]. A few 8-substituted quinoline carboxylic acids, **42** were synthesized by Sanchez et al. that showed antibacterial activity [36]. Upadhayaya et al. developed 3-benzyl-6-bromo-2-methoxy quinoline derivatives, **43,** and these derivatives are active against *Mycobacterium tuberculosis* H37Rv strain [37]. A few analogues of 7-chloro quinolones, **44** were synthesized by De Souza et al., and these derivatives were found to be effective against multidrug-resistant tuberculosis [38]. Lilienkampf et al. synthesized quinoline-based compounds containing an isoxazole unit and side chain, **45** that was active against *Mycobacterium tuberculosis* [39]. The novel hybrid conjugates of N-(7-chloroquinolin-4-yl) piperazine-1-carbothioamide and 1,3,5-triazine derivatives, **30** synthesized by Bhat et al. also showed excellent antibacterial activity against several Gram-positive and Gram-negative microorganisms [40].

#### **3.5 Antitumor**

Some amido-anilinoquinolines, **46** were synthesized by Scott et al. that act as antitumor agents by inhibiting CSF-1R kinase [41]. Certain derivatives of 4-hydroxyquinolines, **47** were synthesized by Mai et al. that showed histone acetyltransferase (HAT) inhibitory activity [42]. A few 3-cyanoquinolines, **48** were developed by Miller et al. as inhibitors of growth factor receptors (IGF-1R) for treating cancer [43]. 4-Anilinoquinolines, **49** were synthesized by Assefa et al. which were found to contain tyrosine kinase inhibitors [44]. Quinoline carboxylic acids, **50** have been synthesized by Chen et al. that act as antitumor compounds by inhibiting insulin-like growth factors [45]. A few c-Met kinase inhibitory quinolones, **51** were developed by Wang et al. with IC50 < 1 nM. These derivatives were found to show the inhibition of c-Met phosphorylation in c-Met-dependent cell lines [46]. Marganakop et al. developed few 6,7,8-substituted thiosemicarbazones of 2-chloro-3-formyl-quinoline derivatives, **52** which exhibit excellent anticancer activities [47]. Recently, some quinoline derivatives, **53** were synthesized as novel Raf kinase inhibitors with potent and selective antitumor activities. These derivatives were synthesized by modifying the structure of sorafenib [48].

**141**

*Quinoline Heterocycles: Synthesis and Bioactivity DOI: http://dx.doi.org/10.5772/intechopen.81239*

*Monascus purpureus*, and *A. flavus* sp. [51].

Certain tetrahydroquinolines, **54** were synthesized by Gholap et al. which were found to possess good antifungal activity against *Candida albicans*, *Fusarium oxysporum*, and *Mucor* fungi [49]. Kharkar et al. synthesized few quinoline derivatives, **55** that show good antifungal properties [50]. Kumar et al. developed few non-azole antimycotic agents having secondary amine attached 2-chloroquinolines, **56** and evaluated their antifungal activity against *Penicillium citrinum*, *Aspergillus niger*,

Several mono- and poly-substituted quinolones, **57–59** synthesized by Fakhfakh

Substituted 2,4-arylquinolines, **63–66** have been synthesized by Rossiter et al. which possess good anthelmintic activity against levamisole-, ivermectin-, and

thiabendazole-resistant strains of *H. contortus* [55].

et al. were found to exhibit activity against HIV-1 [52]. Ghosh et al. synthesized anilidoquinoline derivatives, **60** which were found to possess an excellent antiviral activity against Japanese encephalitis virus [53]. A few quinoline derivatives, **61** possessing the behavior as HIV-1 Tat-TAR interaction inhibitors were synthesized by Chen et al. [45]. Massari et al. synthesized few desfluoroquinolones, **62** for

**3.6 Antifungal**

**3.7 Antiviral**

treating HIV infection [54].

**3.8 Anthelmintic**

*Quinoline Heterocycles: Synthesis and Bioactivity DOI: http://dx.doi.org/10.5772/intechopen.81239*

#### **3.6 Antifungal**

*Heterocycles - Synthesis and Biological Activities*

**3.5 Antitumor**

conjugates of N-(7-chloroquinolin-4-yl) piperazine-1-carbothioamide and 1,3,5-triazine derivatives, **30** synthesized by Bhat et al. also showed excellent antibacterial activity against several Gram-positive and Gram-negative microorganisms [40].

Some amido-anilinoquinolines, **46** were synthesized by Scott et al. that act as

antitumor agents by inhibiting CSF-1R kinase [41]. Certain derivatives of 4-hydroxyquinolines, **47** were synthesized by Mai et al. that showed histone acetyltransferase (HAT) inhibitory activity [42]. A few 3-cyanoquinolines, **48** were developed by Miller et al. as inhibitors of growth factor receptors (IGF-1R) for treating cancer [43]. 4-Anilinoquinolines, **49** were synthesized by Assefa et al. which were found to contain tyrosine kinase inhibitors [44]. Quinoline carboxylic acids, **50** have been synthesized by Chen et al. that act as antitumor compounds by inhibiting insulin-like growth factors [45]. A few c-Met kinase inhibitory quinolones, **51** were developed by Wang et al. with IC50 < 1 nM. These derivatives were found to show the inhibition of c-Met phosphorylation in c-Met-dependent cell lines [46]. Marganakop et al. developed few 6,7,8-substituted thiosemicarbazones of 2-chloro-3-formyl-quinoline derivatives, **52** which exhibit excellent anticancer activities [47]. Recently, some quinoline derivatives, **53** were synthesized as novel Raf kinase inhibitors with potent and selective antitumor activities. These deriva-

tives were synthesized by modifying the structure of sorafenib [48].

**140**

Certain tetrahydroquinolines, **54** were synthesized by Gholap et al. which were found to possess good antifungal activity against *Candida albicans*, *Fusarium oxysporum*, and *Mucor* fungi [49]. Kharkar et al. synthesized few quinoline derivatives, **55** that show good antifungal properties [50]. Kumar et al. developed few non-azole antimycotic agents having secondary amine attached 2-chloroquinolines, **56** and evaluated their antifungal activity against *Penicillium citrinum*, *Aspergillus niger*, *Monascus purpureus*, and *A. flavus* sp. [51].

#### **3.7 Antiviral**

Several mono- and poly-substituted quinolones, **57–59** synthesized by Fakhfakh et al. were found to exhibit activity against HIV-1 [52]. Ghosh et al. synthesized anilidoquinoline derivatives, **60** which were found to possess an excellent antiviral activity against Japanese encephalitis virus [53]. A few quinoline derivatives, **61** possessing the behavior as HIV-1 Tat-TAR interaction inhibitors were synthesized by Chen et al. [45]. Massari et al. synthesized few desfluoroquinolones, **62** for treating HIV infection [54].

#### **3.8 Anthelmintic**

Substituted 2,4-arylquinolines, **63–66** have been synthesized by Rossiter et al. which possess good anthelmintic activity against levamisole-, ivermectin-, and thiabendazole-resistant strains of *H. contortus* [55].

#### **3.9 Antiprotozoal**

2-Propyl quinoline and 2-(3-methyloxiran-2-yl)quinoline alkaloids **67, 68** isolated from *G. longiflora* plant were found to show antileishmanial activity against *Leishmania* spp. [56]. Alkenyl and alkynyl quinolones, **69, 70** reported by Fakhfakh et al. were found to have antiprotozoal activity against cutaneous leishmaniasis, African trypanosomiasis, Chagas disease, and visceral leishmaniasis [52]. Ma et al. developed a few quinolones, **71** that showed activity against *Trypanosoma cruzi* [35].

#### **3.10 Cardiovascular activity**

Srimal et al. demonstrated the hypotensive activity of centhaquin, **72**, and it was found to show the property of reducing the blood pressure in cat in a dose-dependent manner [57]. Quinoline-4-carboxylic acids, **73** have been synthesized by Lloyd et al. that are angiotensin II receptor antagonists and thereby act as hypotensive agents [58]. Certain biarylether amide quinolones, **74** have been developed by Bernotas et al. which act as liver X receptor agonists and are useful in the situation of dyslipidemia [59]. Phenyl acetic acid-based quinolones, **75** have been developed by Hu et al. which act as agonists at liver X receptors and found to have good binding affinity for LXRb and LXRa receptors [60]. A few 4-thiophenyl quinolones, **76** have been developed by Cai et al. that are HMG-CoA reductase inhibitors and useful as hypocholesterolemic agents [61]. Tetrahydroquinolines, **77** which inhibit the cholesteryl ester transfer protein have been synthesized by Rano et al. [62]. Certain tetrahydroquinolinamines, **78** have been developed by Ramos et al. which are found to inhibit platelet aggregation [63].

**143**

**4. Conclusion**

*Quinoline Heterocycles: Synthesis and Bioactivity DOI: http://dx.doi.org/10.5772/intechopen.81239*

Tetrahydroquinolines, **79** have been synthesized by Wallace et al. that are selective estrogen receptor modulators [64]. Bi et al. developed few quinolones, **80** which are potent PDE5 inhibitors thus are useful in the treating erectile dysfunction [65].

Quinolines and quinoline derivatives possess a number of miscellaneous biological activities also. Evans et al. synthesized few quinolones, **81** that are leukotriene synthesis inhibitors [66]. 1,2,3,4-Tetrahydroquinoline-2,2,4-trione oximes, **82** are developed by Cai et al. that act as antagonists of NDMA in glycine receptors and also found to be used as agents against neurodegenerative diseases (e.g., Alzheimer's disease) [61]. Lunniss et al. developed few selective PDE4 inhibitor quinolones **83, 84** which are useful in chronic obstructive pulmonary disorder [67]. Bachiller et al. have developed few tacrine–8-hydroxyquinoline hybrids, **85** that show activity against Alzheimer's [68]. Tetrahydroquinoline-6-yloxy propanes, **86** have been developed by Shakya et al. which show the β-3 agonists [69]. Few aminoalkoxyquinolines, **87** which act as somatostatin receptor subtype-2 agonists have been developed by Wolkenberg et al. which are useful in proliferative diabetic retinopathy and also found utility in exudative age-related macular degeneration [70].

Since quinoline and its derivatives are known for their wide spectrum of pharmacological activities, a number of synthetic methods have been developed from time to time for their synthesis by conventional, homogeneous, and heterogeneous acid-catalyzed methods; rare-earth-catalyzed, transition metal-catalyzed, radicalcatalyzed, microwave-assisted, ultrasound-promoted, or solvent-free conditions, and many more. This book chapter will be very useful to the researcher working in

**3.11 Reproductive system**

**3.12 Miscellaneous**

*Quinoline Heterocycles: Synthesis and Bioactivity DOI: http://dx.doi.org/10.5772/intechopen.81239*

#### **3.11 Reproductive system**

*Heterocycles - Synthesis and Biological Activities*

2-Propyl quinoline and 2-(3-methyloxiran-2-yl)quinoline alkaloids **67, 68** isolated from *G. longiflora* plant were found to show antileishmanial activity against *Leishmania* spp. [56]. Alkenyl and alkynyl quinolones, **69, 70** reported by Fakhfakh et al. were found to have antiprotozoal activity against cutaneous

leishmaniasis, African trypanosomiasis, Chagas disease, and visceral leishmaniasis

Srimal et al. demonstrated the hypotensive activity of centhaquin, **72**, and it was found to show the property of reducing the blood pressure in cat in a dose-dependent manner [57]. Quinoline-4-carboxylic acids, **73** have been synthesized by Lloyd et al. that are angiotensin II receptor antagonists and thereby act as hypotensive agents [58]. Certain biarylether amide quinolones, **74** have been developed by Bernotas et al. which act as liver X receptor agonists and are useful in the situation of dyslipidemia [59]. Phenyl acetic acid-based quinolones, **75** have been developed by Hu et al. which act as agonists at liver X receptors and found to have good

binding affinity for LXRb and LXRa receptors [60]. A few 4-thiophenyl quinolones, **76** have been developed by Cai et al. that are HMG-CoA reductase inhibitors and useful as hypocholesterolemic agents [61]. Tetrahydroquinolines, **77** which inhibit the cholesteryl ester transfer protein have been synthesized by Rano et al. [62]. Certain tetrahydroquinolinamines, **78** have been developed by Ramos et al. which

[52]. Ma et al. developed a few quinolones, **71** that showed activity against

**3.9 Antiprotozoal**

*Trypanosoma cruzi* [35].

**3.10 Cardiovascular activity**

are found to inhibit platelet aggregation [63].

**142**

Tetrahydroquinolines, **79** have been synthesized by Wallace et al. that are selective estrogen receptor modulators [64]. Bi et al. developed few quinolones, **80** which are potent PDE5 inhibitors thus are useful in the treating erectile dysfunction [65].

#### **3.12 Miscellaneous**

Quinolines and quinoline derivatives possess a number of miscellaneous biological activities also. Evans et al. synthesized few quinolones, **81** that are leukotriene synthesis inhibitors [66]. 1,2,3,4-Tetrahydroquinoline-2,2,4-trione oximes, **82** are developed by Cai et al. that act as antagonists of NDMA in glycine receptors and also found to be used as agents against neurodegenerative diseases (e.g., Alzheimer's disease) [61]. Lunniss et al. developed few selective PDE4 inhibitor quinolones **83, 84** which are useful in chronic obstructive pulmonary disorder [67]. Bachiller et al. have developed few tacrine–8-hydroxyquinoline hybrids, **85** that show activity against Alzheimer's [68]. Tetrahydroquinoline-6-yloxy propanes, **86** have been developed by Shakya et al. which show the β-3 agonists [69]. Few aminoalkoxyquinolines, **87** which act as somatostatin receptor subtype-2 agonists have been developed by Wolkenberg et al. which are useful in proliferative diabetic retinopathy and also found utility in exudative age-related macular degeneration [70].

#### **4. Conclusion**

Since quinoline and its derivatives are known for their wide spectrum of pharmacological activities, a number of synthetic methods have been developed from time to time for their synthesis by conventional, homogeneous, and heterogeneous acid-catalyzed methods; rare-earth-catalyzed, transition metal-catalyzed, radicalcatalyzed, microwave-assisted, ultrasound-promoted, or solvent-free conditions, and many more. This book chapter will be very useful to the researcher working in

this field, and it would help them to develop new synthetic methods for the potent quinoline derivatives with good or enhanced biological activities for the future.

### **Acknowledgements**

The author is grateful to DST-SERB for the Early Career Research Award grant (ECR/2016/001041). The author is thankful to SASTRA Deemed University, Thanjavur, for their encouragement and support.

### **Conflict of interest**

The authors declare that there is no conflict of interest.

### **Author details**

Yamajala B.R.D. Rajesh School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur, India

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

© 2018 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.

**145**

*Quinoline Heterocycles: Synthesis and Bioactivity DOI: http://dx.doi.org/10.5772/intechopen.81239*

[1] Kouznetsov VV, Mendez LY, Gomez CM. Recent progress in the synthesis of quinolones. Current Organic Chemistry. 2005;**9**:141-161. DOI: 10.2174/1385272053369196

Letters. 2009;**50**:514-519. DOI: 10.1016/j.

[8] Martinez R, Ramon DJ, Yus M. Transition metal free indirect Friedlander synthesis of quinolines from alcohols. The Journal of Organic Chemistry. 2008;**73**:9778-9780. DOI:

[9] Horn J, Marsden SP, Nelson A, House D, Weingarten GG. Convergent, regiospecific synthesis of quinolines from o-aminophenylboronates. Organic Letters. 2008;**10**:4117-4120. DOI:

[10] Zhou W, Zhang L, Jiao N. The tandem reaction combining radical and ionic processes: An efficient approach to substituted 3,4-dihydroquinolin-2-ones. Tetrahedron. 2009;**65**:1982-1987. DOI:

[11] Wang LM, Hu L, Chen HJ, Sui YY, Shen W. One-pot synthesis of quinoline-4-carboxylic acid derivatives in water: Ytterbium perfluorooctanoate

[12] Kouznetsov VV. Recent synthetic developments in a powerful imino Diels–Alder reaction (Povarov reaction): Application to the synthesis of N-polyheterocycles and related alkaloids. Tetrahedron. 2009;**65**:2721-2750. DOI: 10.1016/j.

[13] Wang Y, Peng C, Liu L, Zhao J, Su L, Zhu Q. Sulfuric acid promoted

2-(2-(trimethylsilyl)ethynyl)anilines with arylaldehydes in alcoholic solvents: An efficient one-pot synthesis of 4-alkoxy-2-arylquinolines. Tetrahedron Letters. 2009;**50**:2261-2265. DOI: 10.1016/j.tetlet.2009.02.206

condensation cyclization of

catalysed Doebner reaction. Journal of Fluorine Chemistry. 2009;**130**:406-409. DOI: 10.1016/j.

jfluchem.2009.01.002

tet.2008.12.059

tetlet.2008.09.097

10.1021/jo801678n

10.1021/ol8016726

10.1016/j.tet.2009.01.027

[2] Chen Y, Zhao Y, Lu C, Tzeng C, Wang JP. Synthesis, cytotoxicity, and antiinflammatory evaluation of 2-(furan-2-yl)-4-(phenoxy)quinoline derivatives. Bioorganic & Medicinal Chemistry. 2006;**14**:4373-4378. DOI:

10.1016/j.bmc.2006.02.039

10.1055/s-0028-1087340

[4] Lekhok KC, Prajapati D, Boruah RC. Indium(III)

trifluoromethanesulfonate: An efficient reusable catalyst for the alkynylation– cyclization of 2-aminoaryl ketones and synthesis of 2,4-disubstituted quinolines. Synlett. 2008;**5**:655-658. DOI: 10.1055/s-2008-1042800

[5] Hegedus A, Hell Z, Vargadi T, Potor A, Gresits I. A new, simple synthesis of 1,2-dihydroquinolines via cyclocondensation using zeolite catalyst. Catalysis Letters. 2007;**117**:99-101. DOI:

[6] Zhou T, Lin J, Chen Z. A convenient synthesis of quinolones via ionic

liquid-catalysed Friedlander annulation. Letters in Organic Chemistry. 2008;**5**:47- 50. DOI: 10.2174/157017808783330261

10.1007/s10562-007-9127-4

[7] Ghassamipour S, Sardarian AR. Friedländer synthesis of polysubstituted quinolines in the presence of dodecylphosphonic acid (DPA) as a highly efficient, recyclable and novel catalyst in aqueous media and solvent-free conditions. Tetrahedron

[3] Sarma R, Prajapati D. Ionic liquid—An efficient recyclable system for the synthesis of 2,4-disubstituted quinolines via Meyer–Schuster rearrangement. Synlett. 2008;**19**:3001-3005. DOI:

**References**

*Quinoline Heterocycles: Synthesis and Bioactivity DOI: http://dx.doi.org/10.5772/intechopen.81239*

#### **References**

*Heterocycles - Synthesis and Biological Activities*

Thanjavur, for their encouragement and support.

The authors declare that there is no conflict of interest.

**Acknowledgements**

**Conflict of interest**

this field, and it would help them to develop new synthetic methods for the potent quinoline derivatives with good or enhanced biological activities for the future.

The author is grateful to DST-SERB for the Early Career Research Award grant

(ECR/2016/001041). The author is thankful to SASTRA Deemed University,

**144**

India

**Author details**

Yamajala B.R.D. Rajesh

provided the original work is properly cited.

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

© 2018 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,

School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur,

[1] Kouznetsov VV, Mendez LY, Gomez CM. Recent progress in the synthesis of quinolones. Current Organic Chemistry. 2005;**9**:141-161. DOI: 10.2174/1385272053369196

[2] Chen Y, Zhao Y, Lu C, Tzeng C, Wang JP. Synthesis, cytotoxicity, and antiinflammatory evaluation of 2-(furan-2-yl)-4-(phenoxy)quinoline derivatives. Bioorganic & Medicinal Chemistry. 2006;**14**:4373-4378. DOI: 10.1016/j.bmc.2006.02.039

[3] Sarma R, Prajapati D. Ionic liquid—An efficient recyclable system for the synthesis of 2,4-disubstituted quinolines via Meyer–Schuster rearrangement. Synlett. 2008;**19**:3001-3005. DOI: 10.1055/s-0028-1087340

[4] Lekhok KC, Prajapati D, Boruah RC. Indium(III) trifluoromethanesulfonate: An efficient reusable catalyst for the alkynylation– cyclization of 2-aminoaryl ketones and synthesis of 2,4-disubstituted quinolines. Synlett. 2008;**5**:655-658. DOI: 10.1055/s-2008-1042800

[5] Hegedus A, Hell Z, Vargadi T, Potor A, Gresits I. A new, simple synthesis of 1,2-dihydroquinolines via cyclocondensation using zeolite catalyst. Catalysis Letters. 2007;**117**:99-101. DOI: 10.1007/s10562-007-9127-4

[6] Zhou T, Lin J, Chen Z. A convenient synthesis of quinolones via ionic liquid-catalysed Friedlander annulation. Letters in Organic Chemistry. 2008;**5**:47- 50. DOI: 10.2174/157017808783330261

[7] Ghassamipour S, Sardarian AR. Friedländer synthesis of polysubstituted quinolines in the presence of dodecylphosphonic acid (DPA) as a highly efficient, recyclable and novel catalyst in aqueous media and solvent-free conditions. Tetrahedron

Letters. 2009;**50**:514-519. DOI: 10.1016/j. tetlet.2008.09.097

[8] Martinez R, Ramon DJ, Yus M. Transition metal free indirect Friedlander synthesis of quinolines from alcohols. The Journal of Organic Chemistry. 2008;**73**:9778-9780. DOI: 10.1021/jo801678n

[9] Horn J, Marsden SP, Nelson A, House D, Weingarten GG. Convergent, regiospecific synthesis of quinolines from o-aminophenylboronates. Organic Letters. 2008;**10**:4117-4120. DOI: 10.1021/ol8016726

[10] Zhou W, Zhang L, Jiao N. The tandem reaction combining radical and ionic processes: An efficient approach to substituted 3,4-dihydroquinolin-2-ones. Tetrahedron. 2009;**65**:1982-1987. DOI: 10.1016/j.tet.2009.01.027

[11] Wang LM, Hu L, Chen HJ, Sui YY, Shen W. One-pot synthesis of quinoline-4-carboxylic acid derivatives in water: Ytterbium perfluorooctanoate catalysed Doebner reaction. Journal of Fluorine Chemistry. 2009;**130**:406-409. DOI: 10.1016/j. jfluchem.2009.01.002

[12] Kouznetsov VV. Recent synthetic developments in a powerful imino Diels–Alder reaction (Povarov reaction): Application to the synthesis of N-polyheterocycles and related alkaloids. Tetrahedron. 2009;**65**:2721-2750. DOI: 10.1016/j. tet.2008.12.059

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[14] Qi C, Zheng Q, Hua R. A domino three-component condensation of ortho-haloacetophenones with urea or amines: A novel one-pot synthesis of halogen-substituted quinolines. Tetrahedron. 2009;**65**:1316-1320. DOI: 10.1016/j.tet.2008.12.039

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**146**

jo902603v

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[51] Kumar S, Bawa S, Drabu S, Panda BP. Design and synthesis of 2-chloroquinoline derivatives as nonazoles antimycotic agents. Medicinal Chemistry Research. 2011;**20**:1340- 1348. DOI: 10.1007/s00044-010-9463-6

[52] Fakhfakh MA, Fournet A, Prina E, Mouscadet JF, Franck X, Hocquemiller R, et al. Synthesis and biological evaluation of substituted quinolines: Potential treatment of protozoal and retroviral co-infections. Bioorganic & Medicinal Chemistry. 2003;**11**:5013- 5023. DOI: 10.1016/j.bmc.2003.09.007

[53] Ghosh J, Swarup V, Saxena A, Das S, Hazra A, Paira P, et al. Therapeutic effect of a novel anilidoquinoline derivative, 2-(2-methyl-quinoline-4ylamino)- N-(2-chlorophenyl)-acetamide, in Japanese encephalitis: Correlation with in vitro neuroprotection. International Journal of Antimicrobial Agents. 2008;**32**:349-354. DOI: 10.1016/j. ijantimicag.2008.05.001

[54] Massari S, Daelemans D, Manfroni G, Sabatini S, Tabarrini O, Pannecouque C, et al. Studies on anti-HIV quinolones: New insights on the C-6 position. Bioorganic & Medicinal Chemistry. 2009;**17**:667-674. DOI: 10.1016/j. bmc.2008.11.056

[55] Rossiter S, Peron SJ, Whitfield PJ, Jones K. Synthesis and anthelmintic properties of arylquinolines with activity against drugresistant nematodes. Bioorganic & Medicinal Chemistry Letters. 2005;**15**:4806-4808. DOI: 10.1016/j.bmcl.2005.07.044

[56] Fournet A, Barrios AA, Munoz V, Hocquemiller R, Cave A, Bruneton J. 2-substituted quinoline alkaloids as potential antileishmanial drugs. Antimicrobial Agents and Chemotherapy. 1993;**37**:859-863. DOI: 10.1128/AAC.37.4.859

[57] Srimal RC, Gulati K, Nityanand S, Dhawan BN. Pharmacological studies on 2-(2-(4-(3-methylphenyl)- 1-piperazinyl) ethyl) quinoline (centhaquin). I. Hypotensive activity. Pharmacological Research. 1990;**22**:319-329. DOI: 10.1016/1043-6618(90)90729-W

[58] Lloyd J, Ryono DE, Bird JE, Buote J, Delaney CL, Dejneka T, et al. Quinoline-4 carboxylic acids as angiotensin II receptor antagonists. Bioorganic & Medicinal Chemistry Letters. 1994;**4**:195-200. DOI: 10.1016/ S0960-894X(01)81146-X

[59] Bernotas RC, Singhaus RR, Kaufman DH, Ullrich J, Fletcher H, Quinet E, et al. Biarylether amide quinolines as liver X receptor agonists. Bioorganic & Medicinal Chemistry. 2009;**17**:1663- 1670. DOI: 10.1016/j.bmc.2008.12.048

[60] Hu B, Jette J, Kaufman D, Singhaus R, Bernotas R, Unwalla R, et al. Further modification on phenyl acetic acid based quinolines as liver X receptor modulators. Bioorganic & Medicinal Chemistry. 2007;**15**:3321-3333. DOI: 10.1016/j.bmc.2007.03.013

[61] Cai Z, Zhou W, Sun L. Synthesis and HMG CoA reductase inhibition of 4-thiophenyl quinolines as potential hypocholesterolemic agents. Bioorganic & Medicinal Chemistry.

2007;**15**:7809-7829. DOI: 10.1016/j. bmc.2007.08.044

[62] Rano TA, McMaster ES, Pelton PD, Yang M, Demarest KT, Kuo GH. Design and synthesis of potent inhibitors of cholesteryl ester transfer protein (CETP) exploiting a 1,2,3,4-tetrahydroquinoline platform. Bioorganic & Medicinal Chemistry Letters. 2009;**19**:2456-2460. DOI: 10.1016/j.bmcl.2009.03.051

[63] Ramos AIM, Mecom JS, Kiesow TJ, Graybill TL, Brown GD, Aiyar NV, et al. Tetrahydro-4-quinolinamines identified as novel P2Y1 receptor antagonists. Bioorganic & Medicinal Chemistry Letters. 2008;**18**:6222-6226. DOI: 10.1016/j.bmcl.2008.09.102

[64] Wallace OB, Lauwers KS, Jones SA, Dodge JA. Tetrahydroquinoline based selective estrogen receptor modulators (SERMs). Bioorganic & Medicinal Chemistry Letters. 2003;**13**:1907-1910. DOI: 10.1016/ S0960-894X(03)00306-8

[65] Bi Y, Stoy P, Adam L, He B, Krupinski J, Normandin D, et al. Quinolines as extremely potent and selective PDE5 inhibitors as potential agents for treatment of erectile dysfunction. Bioorganic & Medicinal Chemistry Letters. 2004;**14**:1577-1580. DOI: 10.1016/j.bmcl.2003.12.090

[66] Evans JF, Leveille C, Mancini JA, Prasit P, Therien M, Zamboni R, et al. 5-lipooxygenase-activating protein is the target of a quinoline class of leukotriene synthesis inhibitors. Molecular Pharmaceutics. 1991;**40**:22-27

[67] Lunniss CJ, Cooper AWJ, Eldred CD, Kranz M, Lindvall M, Lucas FS, et al. Quinolines as a novel structural class of potent and selective PDE4 inhibitors: Optimisation for oral administration. Bioorganic & Medicinal Chemistry Letters. 2009;**19**:1380-1385. DOI: 10.1016/j.bmcl.2009.01.045

[68] Bachiller MIF, Perez C, Munoz GCG, Conde S, Lopez MG, Villarroya M, et al. Novel tacrine–8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer's disease, with neuroprotective, cholinergic, antioxidant, and copper complexing properties. Journal of Medicinal Chemistry. 2010;**53**:4927-4937. DOI: 10.1021/jm100329q

**Chapter 11**

**Abstract**

Millennium

*and Rajendra S. Dongre*

via elemental analysis and FT-IR, <sup>1</sup>

inactive at conc. 31 μg/mL against *E. coli*.

**1. Introduction**

**151**

*E. aerogenes*, 5-oxo-imidazoline, azlactones, medicinal

diazole family owing non-adjacent nitrogens in its skeleton.

Potent Antibacterial Profile of

*Roshan D. Nasare, Mohammad Idrees, Satish S. Kola*

Pharmaceutics and therapeutics industries enforced chemists to seek/discover antibacterial novel heterocycles owing specific bioactivity and innate characteristics

5-oxo-imidazolines assayed in vitro for inherent antimicrobial activity at different concentration against stated bacterial strains and compared with standard chloramphenicol. 5-Oxo-imidazolines (**3a** and **3c**) with 125 μg/mL concentration showed excellent antibacterial profile against Gram-positive bacteria, *B. thuringiensis*, while other derivatives at different concentrations showed moderate antibacterial activity against Gram-positive bacteria, *S. aureus* and *B. thuringiensis*. Gram-negative bacteria like *E. coli* and *E. aerogenes* are tested at higher concentration (1000, 500, and 125 μg/mL) and found good-to-moderate antibacterial activity. Tested products found non-active against *E. aerogenes* for 125, 61, and 31 μg/mL concentration also

**Keywords:** antibacterial, Gram positive/negative, *B. thuringiensis*, *S. aureus*, *E. coli*,

Imidazole is a planer five-member ring with molecular formula **C3N2H4**, containing three carbon atoms and two nitrogen atoms in 1 and 3 skeletal positions as depicted in **Figure 1**. This is an aromatic heterocyclic ring that's classified as a

H-NMR and mass spectra techniques. All

significance. This chapter summarized potent antibacterial profile of 5-oxoimidazolines in the new millennium as an antibacterial against Gram-positive and Gram-negative bacteria viz. *B. thuringiensis*, *S. aureus*, *E. coli*, and *E. aerogenes* is presented in this chapter. 5-(H/Br benzofuran-2-yl)-1-phenyl 1H-pyrazole-3 carbohydrazides are condensed with 4-(arylidene)-2 phenyloxazol-5(4H)-one in acetic acid at elevated temperature to yield product 5-(H/Br benzofuran-2-yl)-N- (4-arylidene-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)-1-phenyl-1H-pyrazole-3 carboxamides. Different substrates like 4-(arylidene)-2-phenyloxazol-5(4H)-one allowed to react with benzaldehyde hippuric acid to yield 5-oxo-imidazolines/ 5-oxo-4,5-dihydroimidazole. All synthesized 5-oxo-imidazolines were characterized

5-Oxo-Imidazolines in the New

[69] Shakya N, Roy KK, Saxena AK. Substituted 1,2,3,4-tetrahydroquinolin-6 yloxypropanes as b3-adrenergic receptor agonists: Design, synthesis, biological evaluation and pharmacophore modeling. Bioorganic & Medicinal Chemistry. 2009;**17**:830-847. DOI: 10.1016/j.bmc.2008.11.030

[70] Wolkenberg SE, Zhao Z, Thut C, Maxwell JW, McDonald TP, Kinose F, et al. Design, synthesis, and evaluation of novel 3,6-diaryl-4 aminoalkoxyquinolines as selective agonists of somatostatin receptor subtype 2. Journal of Medicinal Chemistry. 2011;**54**:2351-2358. DOI: 10.1021/jm101501b

#### **Chapter 11**

*Heterocycles - Synthesis and Biological Activities*

[68] Bachiller MIF, Perez C, Munoz GCG, Conde S, Lopez MG, Villarroya M, et al. Novel tacrine–8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer's disease, with neuroprotective, cholinergic, antioxidant, and copper complexing properties. Journal of Medicinal Chemistry. 2010;**53**:4927-4937. DOI:

10.1021/jm100329q

[69] Shakya N, Roy KK, Saxena AK. Substituted 1,2,3,4-tetrahydroquinolin-6-

10.1016/j.bmc.2008.11.030

10.1021/jm101501b

[70] Wolkenberg SE, Zhao Z, Thut C, Maxwell JW, McDonald TP, Kinose F, et al. Design, synthesis, and evaluation of novel 3,6-diaryl-4 aminoalkoxyquinolines as selective agonists of somatostatin receptor subtype 2. Journal of Medicinal Chemistry. 2011;**54**:2351-2358. DOI:

yloxypropanes as b3-adrenergic receptor agonists: Design, synthesis, biological evaluation and pharmacophore modeling. Bioorganic & Medicinal Chemistry. 2009;**17**:830-847. DOI:

2007;**15**:7809-7829. DOI: 10.1016/j.

[62] Rano TA, McMaster ES, Pelton PD, Yang M, Demarest KT, Kuo GH. Design and synthesis of potent inhibitors of cholesteryl ester transfer protein (CETP) exploiting a 1,2,3,4-tetrahydroquinoline platform. Bioorganic & Medicinal Chemistry Letters. 2009;**19**:2456-2460. DOI: 10.1016/j.bmcl.2009.03.051

[63] Ramos AIM, Mecom JS, Kiesow TJ, Graybill TL, Brown GD, Aiyar NV, et al. Tetrahydro-4-quinolinamines identified as novel P2Y1 receptor antagonists. Bioorganic & Medicinal Chemistry Letters. 2008;**18**:6222-6226. DOI: 10.1016/j.bmcl.2008.09.102

[64] Wallace OB, Lauwers KS, Jones SA, Dodge JA. Tetrahydroquinoline based selective estrogen receptor modulators (SERMs). Bioorganic & Medicinal Chemistry Letters. 2003;**13**:1907-1910. DOI: 10.1016/

S0960-894X(03)00306-8

[65] Bi Y, Stoy P, Adam L, He B, Krupinski J, Normandin D, et al. Quinolines as extremely potent and selective PDE5 inhibitors as potential agents for treatment of erectile dysfunction. Bioorganic & Medicinal Chemistry Letters. 2004;**14**:1577-1580. DOI: 10.1016/j.bmcl.2003.12.090

[66] Evans JF, Leveille C, Mancini JA, Prasit P, Therien M, Zamboni R, et al. 5-lipooxygenase-activating protein is the target of a quinoline class of leukotriene synthesis inhibitors.

Molecular Pharmaceutics. 1991;**40**:22-27

administration. Bioorganic & Medicinal Chemistry Letters. 2009;**19**:1380-1385. DOI: 10.1016/j.bmcl.2009.01.045

[67] Lunniss CJ, Cooper AWJ, Eldred CD, Kranz M, Lindvall M, Lucas FS, et al. Quinolines as a novel structural class of potent and selective PDE4 inhibitors: Optimisation for oral

bmc.2007.08.044

**150**

## Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium

*Roshan D. Nasare, Mohammad Idrees, Satish S. Kola and Rajendra S. Dongre*

#### **Abstract**

Pharmaceutics and therapeutics industries enforced chemists to seek/discover antibacterial novel heterocycles owing specific bioactivity and innate characteristics significance. This chapter summarized potent antibacterial profile of 5-oxoimidazolines in the new millennium as an antibacterial against Gram-positive and Gram-negative bacteria viz. *B. thuringiensis*, *S. aureus*, *E. coli*, and *E. aerogenes* is presented in this chapter. 5-(H/Br benzofuran-2-yl)-1-phenyl 1H-pyrazole-3 carbohydrazides are condensed with 4-(arylidene)-2 phenyloxazol-5(4H)-one in acetic acid at elevated temperature to yield product 5-(H/Br benzofuran-2-yl)-N- (4-arylidene-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)-1-phenyl-1H-pyrazole-3 carboxamides. Different substrates like 4-(arylidene)-2-phenyloxazol-5(4H)-one allowed to react with benzaldehyde hippuric acid to yield 5-oxo-imidazolines/ 5-oxo-4,5-dihydroimidazole. All synthesized 5-oxo-imidazolines were characterized via elemental analysis and FT-IR, <sup>1</sup> H-NMR and mass spectra techniques. All 5-oxo-imidazolines assayed in vitro for inherent antimicrobial activity at different concentration against stated bacterial strains and compared with standard chloramphenicol. 5-Oxo-imidazolines (**3a** and **3c**) with 125 μg/mL concentration showed excellent antibacterial profile against Gram-positive bacteria, *B. thuringiensis*, while other derivatives at different concentrations showed moderate antibacterial activity against Gram-positive bacteria, *S. aureus* and *B. thuringiensis*. Gram-negative bacteria like *E. coli* and *E. aerogenes* are tested at higher concentration (1000, 500, and 125 μg/mL) and found good-to-moderate antibacterial activity. Tested products found non-active against *E. aerogenes* for 125, 61, and 31 μg/mL concentration also inactive at conc. 31 μg/mL against *E. coli*.

**Keywords:** antibacterial, Gram positive/negative, *B. thuringiensis*, *S. aureus*, *E. coli*, *E. aerogenes*, 5-oxo-imidazoline, azlactones, medicinal

#### **1. Introduction**

Imidazole is a planer five-member ring with molecular formula **C3N2H4**, containing three carbon atoms and two nitrogen atoms in 1 and 3 skeletal positions as depicted in **Figure 1**. This is an aromatic heterocyclic ring that's classified as a diazole family owing non-adjacent nitrogens in its skeleton.

**Biological importance of 5-oxo-imidazoline:** Literature survey indicated that the synthetic drugs/molecules incorporated with 5-oxo-imidazoline found to owe assorted biological/clinical significance and wide range of pharmacological activities

*Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium*

*DOI: http://dx.doi.org/10.5772/intechopen.81269*

Solankee et al. [17] synthesized some 5-imidazolinones **(5)** and evaluated as

Mistry et al. [18] have synthesized imidazolinone **(6)** and studied antibacterial,

Kathrotiya et al. [19] and co-workers reported a series of some new quinoline based imidazole-5-one derivatives **(7)** and evaluated them as antibacterial and

Desai et al. [20] also reported the synthesis of 5-oxo-imidazole amides derivatives including quinoline unit **(8)** and assessed their antibacterial and antifungal agent.

as mention below:

anticancer agent.

antifungal activities.

antifungal agent.

**153**

Assorted naturally occurring alkaloids own this imidazole moiety as vital biological building blocks viz; histidine and related hormone histamine. Various synthetic drugs are based on imidazole rings like antifungal, antibiotics: nitroimidazole and sedative: midazolam etc. Oxo-imidazoline derivatives are ketodihydroimidazoles too, known as **imidazolinone** a five member ring system having 2-nitrogen situated at 1 and 3-positions and ─C═O at various positions like 2, 4 and 5 of ring. Three possible isomers of imidazolinone observed based on position of <sup>C</sup>═O substituent at skeleton namely: 2-oxo-imidazoline **(2)**, 4-oxo-imidazoline **(3)** and 5-oxo-imidazoline **(4).**

**5-Oxo-4,5-dihydroimidazole** derivative is called as 5-oxo-imidazoline, unsaturated system, in fact nitrogen analogues of azlactone/oxazolone can be converted into amino acids [1, 2] and also employed active pharmaceutical ingredient/API component in drugs [3]. 5-Oxo-imidazoline holds biological as well as chemical aspects for a long time; among the various heterocycles, it is preferred due to its wide antimicrobial profile. Certain imidazolines are useful intermediates in synthesis of many natural products as well as common building blocks in many biologically active moieties [4].

*Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium DOI: http://dx.doi.org/10.5772/intechopen.81269*

**Biological importance of 5-oxo-imidazoline:** Literature survey indicated that the synthetic drugs/molecules incorporated with 5-oxo-imidazoline found to owe assorted biological/clinical significance and wide range of pharmacological activities as mention below:

Solankee et al. [17] synthesized some 5-imidazolinones **(5)** and evaluated as anticancer agent.

Mistry et al. [18] have synthesized imidazolinone **(6)** and studied antibacterial, antifungal activities.

Kathrotiya et al. [19] and co-workers reported a series of some new quinoline based imidazole-5-one derivatives **(7)** and evaluated them as antibacterial and antifungal agent.

Desai et al. [20] also reported the synthesis of 5-oxo-imidazole amides derivatives including quinoline unit **(8)** and assessed their antibacterial and antifungal agent.

Assorted naturally occurring alkaloids own this imidazole moiety as vital biological building blocks viz; histidine and related hormone histamine. Various synthetic drugs are based on imidazole rings like antifungal, antibiotics:

*Certain potent antibacterial profile of 5-oxo-imidazolines in the new millennium [5–16].*

*Heterocycles - Synthesis and Biological Activities*

nitroimidazole and sedative: midazolam etc. Oxo-imidazoline derivatives are ketodihydroimidazoles too, known as **imidazolinone** a five member ring system having 2-nitrogen situated at 1 and 3-positions and ─C═O at various positions like 2, 4 and 5 of ring. Three possible isomers of imidazolinone observed based on position of <sup>C</sup>═O substituent at skeleton namely: 2-oxo-imidazoline **(2)**, 4-oxo-imidazoline **(3)**

**5-Oxo-4,5-dihydroimidazole** derivative is called as 5-oxo-imidazoline, unsaturated system, in fact nitrogen analogues of azlactone/oxazolone can be converted into amino acids [1, 2] and also employed active pharmaceutical ingredient/API component in drugs [3]. 5-Oxo-imidazoline holds biological as well as chemical aspects for a long time; among the various heterocycles, it is preferred due to its wide antimicrobial profile. Certain imidazolines are useful intermediates in synthesis of many natural products as well as common building blocks in many biologi-

and 5-oxo-imidazoline **(4).**

**Figure 1.**

cally active moieties [4].

**152**

Mohammad and coworkers [21] have prepared some new imidazolinones and investigated their antimicrobial activities. Khan et al. [22] have also reported antibacterial and fungicidal activity of 5-oxo-imidazolines. Herbicidal activity of imidazolinone derivatives have been reported by Andreani et al. [23]. Moreover Zhou et al*.* [24] and Pai et al. [25] have reported anticancer active analogues of 5-oxo-imidazolines. Imidazolinone derivatives which possess antifungal activities have been reported by Shah et al. [26]. Some new 5-oxo-imidazolines as antimicrobial agents have been investigated by Patel et al*.* [27]. Rao [28] have prepared substituted imidazolone derivatives and reported their pharmaceutical use as inhibitors of p38 MAP Kinase and ERK-2 inhibitors. Xue et al. [29] have synthesized and evaluated imidazole-2-one derivatives as potential antitumor agents. Parekh and co-workers [30] have synthesized 5-oxo-imidazolines as novel bioactive compounds derived from benzimidazole. Kanjaria and co-workers [31] have described imidazolinones as potential antimicrobial agents. Joshi et al*.* [3] have synthesized imidazolinones as potent anticonvulsant agents. Acharya et al. [32] tested the imidazolinone **(9)** having quinolone nucleus for their antibacterial activity toward Gram-positive and Gram-negative bacteria and antifungal activity toward *Aspergillus niger* at a concentration of 40 μg, they found active against microorganism.

monitored by E. Merck TLC aluminum sheet silica gel 60F254 and seen spot in UV

*Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium*

(I) **Synthesis of benzoyl glycine [33]:** A solution of glycine (0.33 mol) in 10% NaOH (250 mL) of was prepared and benzoyl chloride (45 mL, 0.385 mol) was added to the above solution in portions. The mixture was shaken vigorously after each addition until all the chlorides have been reacted. The mixture was cooled by adding few grams of crushed ice and was acidified by adding conc. HCl slowly with constant stirring. The resulting crystalline precipitate of benzoyl glycine was filtered and washed with cold water and dried. The solid was treated with hot CCl4 in order to remove benzoic acid. The dried product was recrystallized

(II) **Synthesis of 4-(arylidene)-2-phenyloxazol-5(4***H***)-ones [33] (2a-g)**: Benzoyl glycine (0.0476 mmol), aryl aldehydes (0.0476 mol), acetic anhydride (14 mL, 0.146 mmol) and anhydrous sodium acetate (0.0476 mmol) were placed in a 250 mL conical flask. It was heated on electric hot plate with constant shaking until the mixture liquefies

completely. Then it was refluxed for 2 h on water bath. Then ethanol (10 mL) was added and mixture was allowed to stand

(III) **Preparation of 5-(5-H/Br benzofuran-2-yl)-1-phenyl-1***H***-pyrazole carbohydrazide (1a-b):** Synthesis of (5-(5-H/Br benzofuran-2-yl)-1 phenyl-1*H*-pyrazole-3-carbohydrazides (**1a-b)** were prepared in laboratory

(IV) **General procedure for the synthesis of 5-(5-H/Br benzofuran-2-yl)-***N***- (4-arylidene-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)-1-phenyl-1***H***pyrazole-3 carboxamide (3a-g):** To a mixture of 4-benzylidene-2 phenyloxazol-5(4*H*)-one, **2a** (0.002 mol) and 5-(benzofuran-2-yl)-1 phenyl-1*H*-pyrazole-3-carbohydrazide **1a** (0.002 mol), acetic acid (20 mL) were added and the contents were refluxed for 9 h. Resulting mass was poured onto crushed ice, filtered and the product was recrystallized from

Similarly, other 5-(bromobenzofuran-2-yl)-*N*-(4-arylidene-5-oxo-2-phenyl-4,5 dihydro imidazole-1-yl)-1-phenyl-1*H*-pyrazole-3-carboxamide **3b-g** were synthe-

in quantitative yield according to reference method [34].

sized from **1b** and **2b-g** by extending the same procedure followed for **3a**.

overnight. The crystalline precipitate was filtered, washed with ice-cold alcohol and boiling water. The product was dried and recrystallized using

light and iodine chamber.

*DOI: http://dx.doi.org/10.5772/intechopen.81269*

with boiling water.

benzene.

ethanol to give **3a**.

• **Reaction scheme:**

See **Figures 2** and **3**.

**155**

**3. Experimental**

In view of potent antimicrobial and other pharmacological activities exhibited by 5-oxo-imidazolines, a variety of novel imidazolone analogs (**3a**-**g**) were synthesized by the condensation of different substituted oxazolines (**2a**-**g**) with hetero-aromatic amines (**1a**-**b**). All the synthesized compounds were screened for in vitro activities against a panel of Gram-positive and Gram-negative bacteria.

#### **2. Materials and method**

Melting points of all synthesized compounds were recorded in open capillary tube and are uncorrected. IR was recorded on a Shimadzu IR Spectrophotometer in KBr pellets. 1H-NMR recorded on a Bruker AM 400 model (400 MHz) using tetramethylsilane (TMS) as an internal reference and DMSO-d6 as solvent. Chemical shifts are given in parts per million (ppm). Positive-ion electrospray ionization (ESI) mass spectra were obtained with a Waters MicromassQ–TOF Micro, Mass Spectrophotometer. Elemental analysis was done on Vario EL III Elemental Analyzer, all compounds showed satisfactory elemental analysis. Reactions were

*Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium DOI: http://dx.doi.org/10.5772/intechopen.81269*

monitored by E. Merck TLC aluminum sheet silica gel 60F254 and seen spot in UV light and iodine chamber.

### **3. Experimental**

Mohammad and coworkers [21] have prepared some new imidazolinones and

investigated their antimicrobial activities. Khan et al. [22] have also reported antibacterial and fungicidal activity of 5-oxo-imidazolines. Herbicidal activity of imidazolinone derivatives have been reported by Andreani et al. [23]. Moreover Zhou et al*.* [24] and Pai et al. [25] have reported anticancer active analogues of 5-oxo-imidazolines. Imidazolinone derivatives which possess antifungal activities have been reported by Shah et al. [26]. Some new 5-oxo-imidazolines as antimicrobial agents have been investigated by Patel et al*.* [27]. Rao [28] have prepared substituted imidazolone derivatives and reported their pharmaceutical use as inhibitors of p38 MAP Kinase and ERK-2 inhibitors. Xue et al. [29] have synthesized and evaluated imidazole-2-one derivatives as potential antitumor agents. Parekh and co-workers [30] have synthesized 5-oxo-imidazolines as novel bioactive compounds derived from benzimidazole. Kanjaria and co-workers [31] have described imidazolinones as potential antimicrobial agents. Joshi et al*.* [3] have synthesized imidazolinones as potent anticonvulsant agents. Acharya et al. [32] tested the imidazolinone **(9)** having quinolone nucleus for their antibacterial activity toward Gram-positive and Gram-negative bacteria and antifungal activity toward *Aspergillus niger* at a concentration of 40 μg, they found active against

*Heterocycles - Synthesis and Biological Activities*

In view of potent antimicrobial and other pharmacological activities exhibited by 5-oxo-imidazolines, a variety of novel imidazolone analogs (**3a**-**g**) were synthesized by the condensation of different substituted oxazolines (**2a**-**g**) with hetero-aromatic amines (**1a**-**b**). All the synthesized compounds were

screened for in vitro activities against a panel of Gram-positive and Gram-negative

Melting points of all synthesized compounds were recorded in open capillary tube and are uncorrected. IR was recorded on a Shimadzu IR Spectrophotometer in KBr pellets. 1H-NMR recorded on a Bruker AM 400 model (400 MHz) using tetramethylsilane (TMS) as an internal reference and DMSO-d6 as solvent. Chemical shifts are given in parts per million (ppm). Positive-ion electrospray ionization (ESI) mass spectra were obtained with a Waters MicromassQ–TOF Micro, Mass Spectrophotometer. Elemental analysis was done on Vario EL III Elemental Analyzer, all compounds showed satisfactory elemental analysis. Reactions were

microorganism.

bacteria.

**154**

**2. Materials and method**


Similarly, other 5-(bromobenzofuran-2-yl)-*N*-(4-arylidene-5-oxo-2-phenyl-4,5 dihydro imidazole-1-yl)-1-phenyl-1*H*-pyrazole-3-carboxamide **3b-g** were synthesized from **1b** and **2b-g** by extending the same procedure followed for **3a**.

• **Reaction scheme:**

See **Figures 2** and **3**.

**4-(4-Methoxybenzylidene)-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)-5- (5-bromo benzofuran-2-yl)-1-phenyl-1***H***-pyrazole-3-carboxamide (3b):** Yellow crystalline solid; recrystallization solvent, Ethanol; mp. 132–135°C; yield, 78%; IR

*Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium*

1438 (C═C), 1257, 998 (C─O─C), 1159 (C─N─C stretch), 1649 (C═O in amide group), 1595 (C═N), 1106 (C─N). Elemental anal. calcd: for C35H24BrN5O4; calcu-

**4-(2-Chlorobenzylidene)-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)-5-(5 bromobenzofuran-2-yl)-1-phenyl-1***H***-pyrazole-3-carboxamide (3c):** Yellow crystalline solid; re-crystallization solvent, ethanol; mp. 155–158°C; yield, 82%; IR

1243, 1060 (C─O─C), 1155 (C─N─C stretch), 1643 (C═O in amide group), 1595 (C═N), 1106 (C─N). Elemental anal. calcd: for C34H21BrClN5O3; calculated: N,

**5-(5-Bromobenzofuran-2-yl)-N-(4-(naphthalen-1-ylmethylene)-5-oxo-2 phenyl-4,5-dihydroimidazol-1-yl)-1-phenyl-1***H***-pyrazole-3-carboxamide (3d):** Yellow crystalline solid; recrystallization solvent, ethanol; mp. 136–138°C; yield,

1489, 1431 (C═C), 1236, 1069 (C─O─C), 1151 (C─N─C stretch), 1689 (C═O in amide group), 1593 (C═N), 1151 (C─N). Elemental anal. calcd: for C38H24BrN5O3;

1501, 1438 (C═C), 1249, 998 (C─O─C), 1160 (C─N─C stretch), 1642 (C═O in amide group), 1595 (C═N), 1110 (C─N). Elemental anal. calcd: for C41H28BrN5O4;

**5-(5-Bromobenzofuran-2-yl)-N-(5-oxo-2-phenyl-4-((E)-3-phenylallylidene)-4,5-dihydroimidazol-1-yl)-1-phenyl-1***H***-pyrazole-3-carboxamide (3f):** Yellow crystalline solid; recrystallization solvent, ethanol; mp. 158–160°C;

ole), 1493, 1439 (C═C), 1237, 1068 (C─O─C), 1158 (C─N─C stretch), 1627 (C═<sup>O</sup>

**5-(5-Bromobenzofuran-2-yl)-N-(4-(furan-2-ylmethylene)-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)-1-phenyl-1***H***-pyrazole-3-carboxamide(3g):** Yellow crystalline solid; recrystallization solvent, ethanol; mp. 148–150°C; yield, 83%; IR

(C═C), 1231, 1008 (C─O─C), 1153 (C─N─C stretch), 1641 (C═O in amide group), 1525 (C═N in imidazole), 1079 (C─N). Elemental anal. calcd: for C32H20BrN5O4;

The newly synthesized compounds are soluble in following solvents which are listed in table also identification of newly synthesized compounds has been further confirmed by Lassaigne's test for nitrogen, all compound gives positive test. **Table 1**

represents the structure of all derivatives along with solubility solvent and

in amide group), 1597 (C═N), 1105 (C─N). Elemental anal. calcd: for

C36H24BrN5O3; calculated: N, 10.70; found: N, 10.25.

**4-(4-(Benzyloxy)benzylidene)-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)- 5-(5 bromobenzofuran-2-yl)-1-phenyl-1***H***-pyrazole-3-carboxamide (3e):** Yellow crystalline solid; recrystallization solvent, ethanol; mp. 155–157°C; yield, 80%; IR

): 3315 (NH), 3063 (ArH), 1779, 1720 (C═O imidazole), 1502,

): 3417 (NH), 1786, 1715 (C═O imidazole), 1501, 1433 (C═C),

): 3378 (NH), 3005 (ArH), 1778, (C═O imidazole),

): 3432 (NH), 3062, 2986 (ArH), 1786, 1716 (C═O imidazole),

): 3431 (NH), 3062(ArH), 1783 (C═O imidazole), 1496, 1450

): 3342 (NH), 3034 (ArH), 1783 (C═O imidaz-

(KBr, v max in cm<sup>1</sup>

(KBr, v max in cm<sup>1</sup>

10.56; found: N, 10.11.

(KBr, v max in cm<sup>1</sup>

(KBr, v max in cm<sup>1</sup>

Lassaigne's test.

**157**

76%; IR (KBr, v max in cm<sup>1</sup>

calculated: N, 10.32; found: N, 10.40.

calculated: N, 9.53; found: N, 9.07.

yield, 84%; IR (KBr, v max in cm<sup>1</sup>

calculated: N, 11.32; found: N, 10.96.

**4.2 Common examination of the product**

lated: N, 10.64; found: N, 10.03.

*DOI: http://dx.doi.org/10.5772/intechopen.81269*

**Figure 2.** *Reaction scheme for 5-oxo-imidazoline derivatives.*

#### **Figure 3.**

*3D representation of 5-(benzofuran-2-yl)-*N*-(4-benzylidene-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)-1 phenyl-1*H*-pyrazole-3-carboxamide (compound 3a).*

### **4. Results and discussion**

#### **4.1 Spectral, elemental and physical data of synthesized compounds**

**5-(Benzofuran-2-yl)-***N***-(4-benzylidene-5-oxo-2-phenyl-4,5 dihydroimidazol-1-yl)-1-phenyl-1***H***-pyrazole-3-carboxamide (3a):** Yellow crystalline solid; mp. 200–204°C; yield, 90%.

**IR (KBr, v max in cm<sup>1</sup> ):** 3197 (NH), 3062 (ArH), 1793, 1719 (C═O imidazole), 1597, 1525, 1496, 1448, (C═C), 1207, 1292, 1028 (C─O─C), 1164 (C─N─C stretch), 1640 (C═O in amide group), 1525 (C═N), 1110 (C─N). **<sup>1</sup>**

**H-NMR (DMSO-d6):** δ (ppm) 6.53 (s, 1H, C4 of pyrazole ring), 11.65 (s, 1H, NH of amide group), 7.22–8.37 (m, 21H, ArH + benzofuran ring).

**MS:** *m/z*550 [M+H]<sup>+</sup> , 551 [M+2]+ , 572 [M+Na]+ , 573 [(M+H)+Na]<sup>+</sup> .

**Elemental analysis:** Calcd: for C34H23N5O3; calculated: C, 74.30; H, 4.22; N, 12.74; found: C, 74.16; H, 4.05; N, 12.37.

**4-(4-Methoxybenzylidene)-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)-5- (5-bromo benzofuran-2-yl)-1-phenyl-1***H***-pyrazole-3-carboxamide (3b):** Yellow crystalline solid; recrystallization solvent, Ethanol; mp. 132–135°C; yield, 78%; IR (KBr, v max in cm<sup>1</sup> ): 3315 (NH), 3063 (ArH), 1779, 1720 (C═O imidazole), 1502, 1438 (C═C), 1257, 998 (C─O─C), 1159 (C─N─C stretch), 1649 (C═O in amide group), 1595 (C═N), 1106 (C─N). Elemental anal. calcd: for C35H24BrN5O4; calculated: N, 10.64; found: N, 10.03.

**4-(2-Chlorobenzylidene)-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)-5-(5 bromobenzofuran-2-yl)-1-phenyl-1***H***-pyrazole-3-carboxamide (3c):** Yellow crystalline solid; re-crystallization solvent, ethanol; mp. 155–158°C; yield, 82%; IR (KBr, v max in cm<sup>1</sup> ): 3417 (NH), 1786, 1715 (C═O imidazole), 1501, 1433 (C═C), 1243, 1060 (C─O─C), 1155 (C─N─C stretch), 1643 (C═O in amide group), 1595 (C═N), 1106 (C─N). Elemental anal. calcd: for C34H21BrClN5O3; calculated: N, 10.56; found: N, 10.11.

**5-(5-Bromobenzofuran-2-yl)-N-(4-(naphthalen-1-ylmethylene)-5-oxo-2 phenyl-4,5-dihydroimidazol-1-yl)-1-phenyl-1***H***-pyrazole-3-carboxamide (3d):** Yellow crystalline solid; recrystallization solvent, ethanol; mp. 136–138°C; yield, 76%; IR (KBr, v max in cm<sup>1</sup> ): 3378 (NH), 3005 (ArH), 1778, (C═O imidazole), 1489, 1431 (C═C), 1236, 1069 (C─O─C), 1151 (C─N─C stretch), 1689 (C═O in amide group), 1593 (C═N), 1151 (C─N). Elemental anal. calcd: for C38H24BrN5O3; calculated: N, 10.32; found: N, 10.40.

**4-(4-(Benzyloxy)benzylidene)-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)- 5-(5 bromobenzofuran-2-yl)-1-phenyl-1***H***-pyrazole-3-carboxamide (3e):** Yellow crystalline solid; recrystallization solvent, ethanol; mp. 155–157°C; yield, 80%; IR (KBr, v max in cm<sup>1</sup> ): 3432 (NH), 3062, 2986 (ArH), 1786, 1716 (C═O imidazole), 1501, 1438 (C═C), 1249, 998 (C─O─C), 1160 (C─N─C stretch), 1642 (C═O in amide group), 1595 (C═N), 1110 (C─N). Elemental anal. calcd: for C41H28BrN5O4; calculated: N, 9.53; found: N, 9.07.

**5-(5-Bromobenzofuran-2-yl)-N-(5-oxo-2-phenyl-4-((E)-3-phenylallylidene)-4,5-dihydroimidazol-1-yl)-1-phenyl-1***H***-pyrazole-3-carboxamide (3f):** Yellow crystalline solid; recrystallization solvent, ethanol; mp. 158–160°C; yield, 84%; IR (KBr, v max in cm<sup>1</sup> ): 3342 (NH), 3034 (ArH), 1783 (C═O imidazole), 1493, 1439 (C═C), 1237, 1068 (C─O─C), 1158 (C─N─C stretch), 1627 (C═<sup>O</sup> in amide group), 1597 (C═N), 1105 (C─N). Elemental anal. calcd: for C36H24BrN5O3; calculated: N, 10.70; found: N, 10.25.

**5-(5-Bromobenzofuran-2-yl)-N-(4-(furan-2-ylmethylene)-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)-1-phenyl-1***H***-pyrazole-3-carboxamide(3g):** Yellow crystalline solid; recrystallization solvent, ethanol; mp. 148–150°C; yield, 83%; IR (KBr, v max in cm<sup>1</sup> ): 3431 (NH), 3062(ArH), 1783 (C═O imidazole), 1496, 1450 (C═C), 1231, 1008 (C─O─C), 1153 (C─N─C stretch), 1641 (C═O in amide group), 1525 (C═N in imidazole), 1079 (C─N). Elemental anal. calcd: for C32H20BrN5O4; calculated: N, 11.32; found: N, 10.96.

#### **4.2 Common examination of the product**

The newly synthesized compounds are soluble in following solvents which are listed in table also identification of newly synthesized compounds has been further confirmed by Lassaigne's test for nitrogen, all compound gives positive test. **Table 1** represents the structure of all derivatives along with solubility solvent and Lassaigne's test.

**4. Results and discussion**

**Figure 3.**

**156**

**Figure 2.**

**IR (KBr, v max in cm<sup>1</sup>**

**MS:** *m/z*550 [M+H]<sup>+</sup>

talline solid; mp. 200–204°C; yield, 90%.

*phenyl-1*H*-pyrazole-3-carboxamide (compound 3a).*

*Reaction scheme for 5-oxo-imidazoline derivatives.*

*Heterocycles - Synthesis and Biological Activities*

12.74; found: C, 74.16; H, 4.05; N, 12.37.

1640 (C═O in amide group), 1525 (C═N), 1110 (C─N). **<sup>1</sup>**

**4.1 Spectral, elemental and physical data of synthesized compounds**

**dihydroimidazol-1-yl)-1-phenyl-1***H***-pyrazole-3-carboxamide (3a):** Yellow crys-

*3D representation of 5-(benzofuran-2-yl)-*N*-(4-benzylidene-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)-1-*

1597, 1525, 1496, 1448, (C═C), 1207, 1292, 1028 (C─O─C), 1164 (C─N─C stretch),

**H-NMR (DMSO-d6):** δ (ppm) 6.53 (s, 1H, C4 of pyrazole ring), 11.65 (s, 1H,

, 572 [M+Na]+

**Elemental analysis:** Calcd: for C34H23N5O3; calculated: C, 74.30; H, 4.22; N,

**):** 3197 (NH), 3062 (ArH), 1793, 1719 (C═O imidazole),

, 573 [(M+H)+Na]<sup>+</sup>

.

**5-(Benzofuran-2-yl)-***N***-(4-benzylidene-5-oxo-2-phenyl-4,5-**

NH of amide group), 7.22–8.37 (m, 21H, ArH + benzofuran ring).

, 551 [M+2]+

**Sr. no.**

**159**

5. 6. 7. **Table 1.** *Analysis* 

*characteristics.*

1,4-Dioxane,

 DMSO, THF

Prussian blue coloration

1,4-Dioxane,

 DMSO, THF

Prussian blue coloration

*DOI: http://dx.doi.org/10.5772/intechopen.81269*

*Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium*

**Structure and compound**

 **code**

**Solubility** 1,4-Dioxane,

 DMSO, THF

**Lassaigne's**

Prussian blue coloration

 **test for nitrogen**

**Sr. no.**

**158**

1. 2. 3. 4.

1,4-Dioxane,

 DMSO, THF

Prussian blue coloration

1,4-Dioxane,

1,4-Dioxane,

 DMSO, THF

Prussian blue coloration

 DMSO, THF

Prussian blue coloration

*Heterocycles - Synthesis and Biological Activities*

**Structure and compound**

 **code**

**Solubility** 1,4-Dioxane,

 DMSO, THF

**Lassaigne's**

Prussian blue coloration

 **test for nitrogen**

#### **4.3 Physico-chemical characterization**

The synthesis of the novel compounds **3a-g** is described in the reaction schemes. Purity of the compounds was monitored by TLC technique. The structures of the newly synthesized compounds were confirmed using chemical transformation reaction, physical data, elemental analysis and different spectroscopic techniques such as IR, <sup>1</sup> H NMR and mass. The synthesis of the starting compound, 5-(5-H/Br benzofuran-2-yl)-1-phenyl-1*H*-pyrazole-3-carbohydrazides **(1a-b)** and 4- (arylidene)-2-phenyloxazol-5(4*H*)-ones **(2a-g)** achieved in quantitative yields according to the reference method. The reaction of **1a-b** with **2a-g** (4-(arylidene)- 2-phenyloxazol-5(4*H*)-ones) in acetic acid solvent yields compounds **3a-g**.

IR spectrum of this **3a** showed absorption bands at 3197 cm<sup>1</sup> due to ─NH stretching, disappearance of absorption band due to ─NH2 stretching and two absorption bands at 1719 and 1640 cm<sup>1</sup> for two carbonyl groups of imidazoline and aryl amide respectively indicated that 4-(arylidene)-2-phenyloxazol-5(4*H*)-ones has condensed with 5-(5-H/Br benzofuran-2-yl)-1-phenyl-1*H*-pyrazole-3 carbohydrazides to form **3a**. In addition, <sup>1</sup> H NMR spectrum of **3a** showed singlet at <sup>δ</sup> 10.65 ppm for ─NH group and disappearance of signal due to ─NH2 group in the synthesized compound **3a** which is expected in carbohydrazide **1a** and also exhibited multiplet at δ 7.22–8.37 ppm due to 21 aromatic protons is in consistent with aromatic protons of **3a**. The % of elements in **3a** was C 74.16, H 4.05 and N 12.37, while its mass spectrum shows molecular ion peaks at *m/z* 550 [M+H]<sup>+</sup> , 551 [M+2]+ , 572 [M+Na]<sup>+</sup> , 573 [(M+H)+Na].<sup>+</sup> which is in good agreement with the proposed structure and molecular formula C34H23N5O3.

containing microbial culture was allowed to solidify. The discs were then applied and the plates were incubated at 37°C for 24 h (bacteria) and the inhibition zone was measured as diameter in four directions and expressed as mean. The results were compared using chloramphenicol as a standard antibacterial agent. The results of antibacterial activity (i.e. zone of inhibition in mm) are given in the

*Antibacterial drug mechanism in cell wall of microbe. Source: Google image.*

*Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium*

*DOI: http://dx.doi.org/10.5772/intechopen.81269*

**4.6 Inhibition profile zone for Gram-positive bacterial strains of tested**

activity using agar disc-diffusion method against two Gram-positive bacterial

**Compd. code Conc. (μg/mL) Conc. (μg/mL)**

*Bold value indicates activity of tested compound is equal or high than standard drug.*

**3a** 15 14 12 **18** 12 10 14 12 16 12 **18** 15 **3b** 16 15 11 **16** 9 9 16 11 11 8 12 — **3c** 14 15 12 **17** 11 8 16 14 16 11 14 13 **3d** 16 13 12 14 8 — 13 12 14 10 12 11 **3e** 13 11 13 12 11 — 14 13 13 10 11 10 **3f** 14 14 11 10 10 8 13 12 10 — 9 — **3 g** 17 16 13 11 12 10 15 15 14 17 9 7 **Std. drug 22 20 21 16 15 16 26 30 27 21 18 20**

The synthesized compounds **3a-g** were screened for their *in vitro* antimicrobial

**Zone of inhibition (mm) Gram-positive bacteria** *B. thuringiensis S. aureus*

**1000 500 250 125 63 31 1000 500 250 125 63 31**

**Tables 2** and **3**.

**Figure 4.**

**compound-3a-g**

*Standard drug: chloramphenicol.*

*Antibacterial activity of 3a-g.*

**Table 2.**

**161**

Similarly other imidazolinones (**3b-g**) were also identified on the basis of chemical transformation reaction, physical data, IR and elemental detection. IR spectra of each compound showed characteristics absorption bands for ─NH stretching and disappearance of absorption band due to ─NH2 stretching, also showed corresponding band for carbonyl group. Elemental analysis was carried for nitrogen and sulfur of all compounds is found to be in good agreement with the calculated values.

#### **4.4 Antimicrobial activity/profile**

Antimicrobial activity means activity of any agent or drug against microbial organism. Microbial organism includes bacteria, viruses, fungi and protozoa. On the basis of their activity against specific microbial organism they termed as like antibacterial (against bacteria) that means they are capable to inhibit the growth of bacteria or to kill the bacteria. Other term is antifungal (against fungi), antiviral (against virus), antiprotozoal (against protozoa). Heterocyclic entities possess different antimicrobial activity. Activity changes by changing structural unit. It is very interesting thing to check out antimicrobial activity of newly synthesized compound. We carried out antibacterial activity of the novel compound (**Figure 4**).

#### **4.5 Potent antibacterial/inhibition profile of 5-oxo-imidazolines (at different concentration) by agar disc-diffusion method**

Test solutions were prepared with known weight of compound in DMSO and half diluted suitably to give the resultant concentration of 31–1000 μg/mL [35]. Whatman No. 1 sterile filter paper discs (6 mm) were impregnated with solution and allowed to dry at room temperature. *In-vitro* antibacterial activity was determined by using Mueller Hinton Agar obtained from Himedia Ltd., Mumbai. Petri plates were prepared by pouring 10 mL of Mueller Hinton Agar for bacteria

*Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium DOI: http://dx.doi.org/10.5772/intechopen.81269*

#### **Figure 4.** *Antibacterial drug mechanism in cell wall of microbe. Source: Google image.*

containing microbial culture was allowed to solidify. The discs were then applied and the plates were incubated at 37°C for 24 h (bacteria) and the inhibition zone was measured as diameter in four directions and expressed as mean. The results were compared using chloramphenicol as a standard antibacterial agent. The results of antibacterial activity (i.e. zone of inhibition in mm) are given in the **Tables 2** and **3**.

#### **4.6 Inhibition profile zone for Gram-positive bacterial strains of tested compound-3a-g**

The synthesized compounds **3a-g** were screened for their *in vitro* antimicrobial activity using agar disc-diffusion method against two Gram-positive bacterial


*Standard drug: chloramphenicol.*

*Bold value indicates activity of tested compound is equal or high than standard drug.*

### **Table 2.**

*Antibacterial activity of 3a-g.*

**4.3 Physico-chemical characterization**

*Heterocycles - Synthesis and Biological Activities*

carbohydrazides to form **3a**. In addition, <sup>1</sup>

proposed structure and molecular formula C34H23N5O3.

**concentration) by agar disc-diffusion method**

, 572 [M+Na]<sup>+</sup>

**4.4 Antimicrobial activity/profile**

such as IR, <sup>1</sup>

[M+2]+

values.

**160**

The synthesis of the novel compounds **3a-g** is described in the reaction schemes. Purity of the compounds was monitored by TLC technique. The structures of the newly synthesized compounds were confirmed using chemical transformation reaction, physical data, elemental analysis and different spectroscopic techniques

benzofuran-2-yl)-1-phenyl-1*H*-pyrazole-3-carbohydrazides **(1a-b)** and 4- (arylidene)-2-phenyloxazol-5(4*H*)-ones **(2a-g)** achieved in quantitative yields according to the reference method. The reaction of **1a-b** with **2a-g** (4-(arylidene)-

2-phenyloxazol-5(4*H*)-ones) in acetic acid solvent yields compounds **3a-g**. IR spectrum of this **3a** showed absorption bands at 3197 cm<sup>1</sup> due to ─NH stretching, disappearance of absorption band due to ─NH2 stretching and two absorption bands at 1719 and 1640 cm<sup>1</sup> for two carbonyl groups of imidazoline and aryl amide respectively indicated that 4-(arylidene)-2-phenyloxazol-5(4*H*)-ones has condensed with 5-(5-H/Br benzofuran-2-yl)-1-phenyl-1*H*-pyrazole-3-

<sup>δ</sup> 10.65 ppm for ─NH group and disappearance of signal due to ─NH2 group in the synthesized compound **3a** which is expected in carbohydrazide **1a** and also exhibited multiplet at δ 7.22–8.37 ppm due to 21 aromatic protons is in consistent with aromatic protons of **3a**. The % of elements in **3a** was C 74.16, H 4.05 and N 12.37, while its mass spectrum shows molecular ion peaks at *m/z* 550 [M+H]<sup>+</sup>

Similarly other imidazolinones (**3b-g**) were also identified on the basis of chemical transformation reaction, physical data, IR and elemental detection. IR spectra of each compound showed characteristics absorption bands for ─NH stretching and

corresponding band for carbonyl group. Elemental analysis was carried for nitrogen and sulfur of all compounds is found to be in good agreement with the calculated

Antimicrobial activity means activity of any agent or drug against microbial organism. Microbial organism includes bacteria, viruses, fungi and protozoa. On the basis of their activity against specific microbial organism they termed as like antibacterial (against bacteria) that means they are capable to inhibit the growth of bacteria or to kill the bacteria. Other term is antifungal (against fungi), antiviral (against virus), antiprotozoal (against protozoa). Heterocyclic entities possess different antimicrobial activity. Activity changes by changing structural unit. It is very interesting thing to check out antimicrobial activity of newly synthesized compound. We carried out antibacterial activity of the novel compound (**Figure 4**).

**4.5 Potent antibacterial/inhibition profile of 5-oxo-imidazolines (at different**

Test solutions were prepared with known weight of compound in DMSO and half diluted suitably to give the resultant concentration of 31–1000 μg/mL [35]. Whatman No. 1 sterile filter paper discs (6 mm) were impregnated with solution and allowed to dry at room temperature. *In-vitro* antibacterial activity was determined by using Mueller Hinton Agar obtained from Himedia Ltd., Mumbai. Petri plates were prepared by pouring 10 mL of Mueller Hinton Agar for bacteria

disappearance of absorption band due to ─NH2 stretching, also showed

, 573 [(M+H)+Na].<sup>+</sup> which is in good agreement with the

H NMR and mass. The synthesis of the starting compound, 5-(5-H/Br

H NMR spectrum of **3a** showed singlet at

, 551

strains such as *B. thuringiensis, S. aureus.* Chloramphenicol was used as standard drug for bacteria. According to antibacterial data obtained the test compounds **3a**–**c** at 125 μg/mL conc. showed excellent activity i.e. equal or higher than the standard drug and other derivatives viz. **3d**–**g** at 125 μg/mL conc. showed good inhibitory activity against *B. thuringiensis*. At conc. 1000, 500, and 250 μg/mL imidazolinone derivatives 3a-g showed good to moderate activity against *B. thuringiensis*, whereas **3d** and **3e** are found to be inactive at 31 μg/mL against Gram-positive bacteria, *B. thuringiensis*. In case of *S. aureus* **3a** exhibit with excellent activity at 63 μg/mL conc. While at 1000, 500, 250 μg/mL concentrations **3a-g** possesses good to moderate activity. Whereas **3b & 3f** are found to be inactive at 31 μg/mL also **3f** found to be inactive at 125 μg/mL against *S. aureus*. Obtained results of *in-vitro* antimicrobial activities of **3a-h** are summarized in **Table 2**.

**4.7 Inhibition profile zone for Gram-negative bacterial strains of tested**

*Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium*

**Compd. code Conc. (μg/mL) Conc. (μg/mL)**

**3a** 14 10 12 15 12 — 10 12 10 **— —— 3b** 11 11 9 12 — — 12 11 13 8 — — **3c** 18 14 11 13 8 — 13 13 12 10 8 — **3d** 13 12 10 12 10 8 10 9 10 — —— **3e** 15 12 8 10 — — 9 10 11 — —— **3f** 14 10 12 13 9 9 11 12 8 9 — — **3 g** 15 13 12 14 10 8 12 10 9 7 8 — **Std. drug 24 20 18 17 17 21 16 16 17 16 15 15**

The synthesized compounds **3a-g** were screened for their *in vitro* antimicrobial activity using agar disc-diffusion method against two Gram-negative bacterial strains such as *E. coli, E. aerogenes.* Chloramphenicol was used as standard drug for bacteria. According to antibacterial data obtained the test compounds **3a-g** possesses good to moderate activity at higher concentrations, i.e. 1000, 500, 250 and 125 μg/mL against Gram-negative bacteria *E. coli.* At conc. 63 μg/mL **3a-g** showed good activity while **3b** & **3e** found to be inactive against *E. coli*. At conc. 31 μg/mL **3d, 3f & 3g** showed moderate activity whereas **3a, 3b, 3c & 3e** found to be inactive against *E. coli*. In case of *E. aerogenes,* tested compounds showed moderate activity at higher concentrations while poor activity at lower concentrations. At conc. 125 μg/mL **3a, 3d, 3e** and at 63 μg/mL **3a, 3b, 3d, 3e, 3f** found to be inactive. All the compounds were inactive at a concentration of 31 μg/mL against *E. aerogenes.* Obtained results of *in-vitro* antimicrobial activities of synthesized 5-oxo-

> **Zone of inhibition (mm) Gram-negative bacteria** *E. coli E. aerogenes*

**1000 500 250 125 63 31 1000 500 250 125 63 31**

**compound-3a-g**

*DOI: http://dx.doi.org/10.5772/intechopen.81269*

*Standard drug: chloramphenicol.*

**Table 3.**

**163**

imidazolines (**3a-g)** are summarized in **Table 3**.

*Bold value indicates activity of tested compound is equal or high than standard drug.*

*Antibacterial activity of 5-oxo-imidazoline compounds (3a-g).*

#### **4.7 Inhibition profile zone for Gram-negative bacterial strains of tested compound-3a-g**

The synthesized compounds **3a-g** were screened for their *in vitro* antimicrobial activity using agar disc-diffusion method against two Gram-negative bacterial strains such as *E. coli, E. aerogenes.* Chloramphenicol was used as standard drug for bacteria. According to antibacterial data obtained the test compounds **3a-g** possesses good to moderate activity at higher concentrations, i.e. 1000, 500, 250 and 125 μg/mL against Gram-negative bacteria *E. coli.* At conc. 63 μg/mL **3a-g** showed good activity while **3b** & **3e** found to be inactive against *E. coli*. At conc. 31 μg/mL **3d, 3f & 3g** showed moderate activity whereas **3a, 3b, 3c & 3e** found to be inactive against *E. coli*. In case of *E. aerogenes,* tested compounds showed moderate activity at higher concentrations while poor activity at lower concentrations. At conc. 125 μg/mL **3a, 3d, 3e** and at 63 μg/mL **3a, 3b, 3d, 3e, 3f** found to be inactive. All the compounds were inactive at a concentration of 31 μg/mL against *E. aerogenes.* Obtained results of *in-vitro* antimicrobial activities of synthesized 5-oxoimidazolines (**3a-g)** are summarized in **Table 3**.


*Standard drug: chloramphenicol.*

*Bold value indicates activity of tested compound is equal or high than standard drug.*

#### **Table 3.**

strains such as *B. thuringiensis, S. aureus.* Chloramphenicol was used as standard drug for bacteria. According to antibacterial data obtained the test compounds **3a**–**c** at 125 μg/mL conc. showed excellent activity i.e. equal or higher than the standard drug and other derivatives viz. **3d**–**g** at 125 μg/mL conc. showed good inhibitory activity against *B. thuringiensis*. At conc. 1000, 500, and 250 μg/mL imidazolinone derivatives 3a-g showed good to moderate activity against *B. thuringiensis*, whereas **3d** and **3e** are found to be inactive at 31 μg/mL against Gram-positive bacteria, *B. thuringiensis*. In case of *S. aureus* **3a** exhibit with excellent activity at 63 μg/mL conc. While at 1000, 500, 250 μg/mL concentrations **3a-g** possesses good to moderate activity. Whereas **3b & 3f** are found to be inactive at 31 μg/mL also **3f** found to be inactive at 125 μg/mL against *S. aureus*. Obtained results of *in-vitro*

antimicrobial activities of **3a-h** are summarized in **Table 2**.

*Heterocycles - Synthesis and Biological Activities*

**162**

*Antibacterial activity of 5-oxo-imidazoline compounds (3a-g).*

Also, alteration like discharge of molecules from interior of *B. thuringiensis*, *S. aureus* bacterial cell inhibits respiration and increased water uptake may leads to cell death. Gram-positive bacteria own too thick cell wall and deny easy access of 5-oxoimidazoles via their bacterial cell membrane, thus less effective on *E. coli* and *E. aerogenes* series of bacteria. The inhibition profile zone for four different bacterial strains of tested compound-**3a** (at different concentration) 5-oxo-imidazoline com-

*Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium*

Assorted antibacterial agents own certain limitations viz.; resistance/potency, vast types and numbers own different structures besides slightly dissimilar pattern of activity which made it necessary to discover/explore the existing class and functions of almost all the antibacterial agents. Thus, futuristic pathogenic bacterial infections/diseases can be easily cured via promising antibacterial chemotherapeutic agents derive from 5-oxo-Imidazole skeleton. Pursued chapter described

antibacterial resistance of 5-oxo-imidazoles mostly against Gram-positive series like *B. thuringiensis*, *S. aureus*. 5-Oxo-imidazoles can act onto simple one-celled bacterial organism that could kill, inhibit, or at least slower down their growth and ultimately can inhibit concern diseases/infections. This chapter focused on helping futuristic

corresponding biological screening of innate activity of certain novel imidazolinone heterocycles. These synthesized 5-oxo-imidazoles restrain potent antibacterial activity may own prospective different therapeutic behavior if developed as advanced drug moiety. Therefore, chapter focus on the basis of chemical structure of 5-oxo-imidazoles. Gram-positive and Gram-negative bacteria showed varied

Targeted 5-oxo-imidazolines (**3a-g**) a class of imidazolinones are successfully synthesized in good yields and purity checked by physical, analytical and spectral data. Antibacterial screening of 5-oxo-imidazolines (**3a-g**) exhibited a potent bactericidal. Thus, 5-oxo-imidazolines could be powerfully stimulates major advances in remarkable significant chemotherapeutics in medicine, biology and pharmacy. Overall these imidazolinones disturb macromolecules like cytoplasmic membrane covering cytoplasm which acts selective barrier to control internal composition of cell. 5-Oxo-imidazoles in particular interrupted such functional roles of cytoplasmic membrane and ionic outflow that resulted cell destruction/death. Synthesized potent bioactive 5-oxo-imidazoles may open new possibilities in the successful treatment of several diseases due to promising antibacterial profile. So, ample scope exists in further research of imidazolinones especially innate selectivity of 5-oxoimidazoles needs to carry out their chemotherapy as potent antibacterial aims to target cell membrane of range of Gram-negative bacteria as to derive novel drugs of

The authors are thankful to The Principal, Government Science College, Gadchiroli and Dr. N. J. Siddiqui, for his support and cooperation. The authors are also thankful to Dr. S. D. Narkhede, Head, Department of Botany, GSC, Gadchiroli for permitting to carry out the antimicrobial activity, similarly the authors are also thankful to the Director, SAIF, Punjab University, Chandigarh for providing CHN

researchers, clinicians, and academicians involved in synthesizing and

response/susceptibility toward 5-oxo-imidazoles.

HNMR and mass spectra.

pounds are shown in **Figure 5**.

*DOI: http://dx.doi.org/10.5772/intechopen.81269*

**5. Conclusion**

new millennium.

analysis, IR, <sup>1</sup>

**165**

**Acknowledgements**

#### **4.8 Mechanism of inhibition/prohibition**

Gram-negative bacteria habitually owe low susceptibility as outer membrane of their cell wall not gets blocked/penetrated by drugs easily and factors like amount of peptidoglycan, receptors, and lipids availability, nature of cross-linking, autolytic enzymes activity greatly influence the bio-activity, permeation, and incorporation of the antibacterial drugs. 5-Oxo-imidazoles showed their specificity for polysaccharides, thats present in the outer membrane of many Gram-negative bacteria and so acted selectively toxic for series of *B. thuringiensis*, *S. aureus* bacteria. Mechanistically, once alliance with lipopolysaccharide substrate in outer membrane of *B. thuringiensis*, *S. aureus* bacteria, synthesized imidazolinone: potent antibacterial agent changes their membrane structure, thus enhances permeability and disruption of osmotic balance that ultimately results higher physiological effects.

*Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium DOI: http://dx.doi.org/10.5772/intechopen.81269*

Also, alteration like discharge of molecules from interior of *B. thuringiensis*, *S. aureus* bacterial cell inhibits respiration and increased water uptake may leads to cell death. Gram-positive bacteria own too thick cell wall and deny easy access of 5-oxoimidazoles via their bacterial cell membrane, thus less effective on *E. coli* and *E. aerogenes* series of bacteria. The inhibition profile zone for four different bacterial strains of tested compound-**3a** (at different concentration) 5-oxo-imidazoline compounds are shown in **Figure 5**.

#### **5. Conclusion**

**4.8 Mechanism of inhibition/prohibition**

*Heterocycles - Synthesis and Biological Activities*

**Figure 5.**

**164**

Gram-negative bacteria habitually owe low susceptibility as outer membrane of their cell wall not gets blocked/penetrated by drugs easily and factors like amount of peptidoglycan, receptors, and lipids availability, nature of cross-linking, autolytic enzymes activity greatly influence the bio-activity, permeation, and incorporation of the antibacterial drugs. 5-Oxo-imidazoles showed their specificity for polysaccharides, thats present in the outer membrane of many Gram-negative bacteria and so acted selectively toxic for series of *B. thuringiensis*, *S. aureus* bacteria. Mechanistically, once alliance with lipopolysaccharide substrate in outer membrane of *B. thuringiensis*, *S. aureus* bacteria, synthesized imidazolinone: potent antibacterial

agent changes their membrane structure, thus enhances permeability and disruption of osmotic balance that ultimately results higher physiological effects.

*Inhibition profile zone for four different bacterial strains of tested compound-3a (at different concentration).*

Assorted antibacterial agents own certain limitations viz.; resistance/potency, vast types and numbers own different structures besides slightly dissimilar pattern of activity which made it necessary to discover/explore the existing class and functions of almost all the antibacterial agents. Thus, futuristic pathogenic bacterial infections/diseases can be easily cured via promising antibacterial chemotherapeutic agents derive from 5-oxo-Imidazole skeleton. Pursued chapter described antibacterial resistance of 5-oxo-imidazoles mostly against Gram-positive series like *B. thuringiensis*, *S. aureus*. 5-Oxo-imidazoles can act onto simple one-celled bacterial organism that could kill, inhibit, or at least slower down their growth and ultimately can inhibit concern diseases/infections. This chapter focused on helping futuristic researchers, clinicians, and academicians involved in synthesizing and corresponding biological screening of innate activity of certain novel imidazolinone heterocycles. These synthesized 5-oxo-imidazoles restrain potent antibacterial activity may own prospective different therapeutic behavior if developed as advanced drug moiety. Therefore, chapter focus on the basis of chemical structure of 5-oxo-imidazoles. Gram-positive and Gram-negative bacteria showed varied response/susceptibility toward 5-oxo-imidazoles.

Targeted 5-oxo-imidazolines (**3a-g**) a class of imidazolinones are successfully synthesized in good yields and purity checked by physical, analytical and spectral data. Antibacterial screening of 5-oxo-imidazolines (**3a-g**) exhibited a potent bactericidal. Thus, 5-oxo-imidazolines could be powerfully stimulates major advances in remarkable significant chemotherapeutics in medicine, biology and pharmacy. Overall these imidazolinones disturb macromolecules like cytoplasmic membrane covering cytoplasm which acts selective barrier to control internal composition of cell. 5-Oxo-imidazoles in particular interrupted such functional roles of cytoplasmic membrane and ionic outflow that resulted cell destruction/death. Synthesized potent bioactive 5-oxo-imidazoles may open new possibilities in the successful treatment of several diseases due to promising antibacterial profile. So, ample scope exists in further research of imidazolinones especially innate selectivity of 5-oxoimidazoles needs to carry out their chemotherapy as potent antibacterial aims to target cell membrane of range of Gram-negative bacteria as to derive novel drugs of new millennium.

#### **Acknowledgements**

The authors are thankful to The Principal, Government Science College, Gadchiroli and Dr. N. J. Siddiqui, for his support and cooperation. The authors are also thankful to Dr. S. D. Narkhede, Head, Department of Botany, GSC, Gadchiroli for permitting to carry out the antimicrobial activity, similarly the authors are also thankful to the Director, SAIF, Punjab University, Chandigarh for providing CHN analysis, IR, <sup>1</sup> HNMR and mass spectra.

*Heterocycles - Synthesis and Biological Activities*

#### **Author details**

Roshan D. Nasare<sup>1</sup> \*, Mohammad Idrees<sup>2</sup> , Satish S. Kola<sup>3</sup> and Rajendra S. Dongre<sup>4</sup> 1 Department of Chemistry, G. H. Raisoni University, Chhindwara, M.P., India 2 Department of Chemistry, Government Institute of Science, Nagpur, M.H., India 3 Department of Chemistry, Government Science College, Gadchiroli, M.H., India 4 Department of Chemistry, R.T.M., Nagpur University, Nagpur, M.H., India \*Address all correspondence to: nasare.roshan17@gmail.com

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[14] Sidney WF. Chemistry of the biologically important imidazoles. Chemical Reviews, 2002;**32**(1)

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[3] Joshi H, Upadhyay P, Karia D, Baxi AG. Synthesis of some novel imidazolinones as potent anticonvulsant agents. European Journal of Medicinal

Chemistry. 2003;**38**:837

[4] Fox SW. Chemistry of the biologically important Imidazoles. Chemical Reviews. 1943;**32**:479

[5] El-Hady HA, Abubshait SA.

[6] Maneshwar T, Vijethal N,

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Balakrishna V, Kumar CV, Suresh M. Synthesis, characterization and anthelmintic activity of novel isatin substituted imidazoline derivatives. International Journal of Pharmaceutics.

[7] Kalluraya B, Gunaga P, Banji D, Isloor AM. Synthesis and biological studies of some imidazolinone derivatives. Bollettino Chimico Farmaceutico. 2001;**140**:428

[8] Moorthy NS, Saxena V, Karthikeyan

C, Trivedi P. Synthesis, in silico metabolic and toxicity prediction of some novel imidazolinones derivatives as potent anticonvulsant agents. Journal of Enzyme Inhibition and Medicinal

Chemistry. 2012;**27**:201

**167**

<sup>© 2020</sup> 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.

*Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium DOI: http://dx.doi.org/10.5772/intechopen.81269*

#### **References**

[1] Kidwai AR, Dewasia GMV. A New Method for the Synthesis of Amino Acids. Synthesis of Amino Acids and Their Derivatives through 2, 4- Disubstituted 2-Imidazolin-5-ones. Journal of the American Chemical Society. 1962;**27**:4527

[2] Devasia M, Pillai C. An improved method for the synthesis of cylamino acids through 2,4- disubstituted 2 imidazolin-5-ones. Tetrahedron Letters. 1975;**6**:4051

[3] Joshi H, Upadhyay P, Karia D, Baxi AG. Synthesis of some novel imidazolinones as potent anticonvulsant agents. European Journal of Medicinal Chemistry. 2003;**38**:837

[4] Fox SW. Chemistry of the biologically important Imidazoles. Chemical Reviews. 1943;**32**:479

[5] El-Hady HA, Abubshait SA. Synthesis and anticancer evaluation of imidazolinone and benzoxazole derivatives. Research on Chemical Intermediates. 2015;**41**:1833

[6] Maneshwar T, Vijethal N, Balakrishna V, Kumar CV, Suresh M. Synthesis, characterization and anthelmintic activity of novel isatin substituted imidazoline derivatives. International Journal of Pharmaceutics. 2014;**4**:437

[7] Kalluraya B, Gunaga P, Banji D, Isloor AM. Synthesis and biological studies of some imidazolinone derivatives. Bollettino Chimico Farmaceutico. 2001;**140**:428

[8] Moorthy NS, Saxena V, Karthikeyan C, Trivedi P. Synthesis, in silico metabolic and toxicity prediction of some novel imidazolinones derivatives as potent anticonvulsant agents. Journal of Enzyme Inhibition and Medicinal Chemistry. 2012;**27**:201

[9] Mehta P, Davadra P, Shah N, Joshi H. Synthesis and antimicrobial activity of some new imidazolinone derivatives containing benzimidazole, International Letters of Chemistry, Physics and Astronomy. 2014;**29**:74

[10] Biplab D, Jayanta KG, Venkatapuram SS. Synthesis of some oxazolinones and imidazolinones and their antimicrobial screening. Acta Pharmaceutica. 2005;**55**:287

[11] Desai NC, Bhavsar AM, Baldaniya BB. Synthesis and antimicrobial activity of 5-imidazolinone derivatives. Indian Journal of Pharmaceutical Sciences. 2009;**71**:90

[12] Omar AM, Nada MA, Hamdi MH, Ahmad S, Abu SM. Synthesis and Biological Activity Evaluation of Some New Heterocyclic Spirocompounds with Imidazolinone and Pyrazoline Moieties. International Journal of Chemistry. 2011;**3**:20

[13] Mohd A, Arun K, Israr A, Khan SA. Synthesis of pharmaceutically important 1,3,4-Thiadiazole and imidazolinone derivatives as antimicrobial. Indian Journal of Chemistry. 2009;**48**:1288

[14] Sidney WF. Chemistry of the biologically important imidazoles. Chemical Reviews, 2002;**32**(1)

[15] Wadekar MP, Raut AR, Murhekar GH. Synthesis of some novel substituted 5-oxo imidazolines containing azo linkages and their biological screening. Der Pharma Chemica. 2010;**2**:76

[16] He L-W, Dai W-C, Li N-g. Development of orally active thrombin inhibitors for the treatment of thrombotic disorder diseases. Molecules. 2015;**20**:11046

[17] Solankee A, Kapadiya K, Upadhyay K, Patel J. Synthesis and Anticancer

**Author details**

Roshan D. Nasare<sup>1</sup>

**166**

\*, Mohammad Idrees<sup>2</sup>

*Heterocycles - Synthesis and Biological Activities*

\*Address all correspondence to: nasare.roshan17@gmail.com

provided the original work is properly cited.

1 Department of Chemistry, G. H. Raisoni University, Chhindwara, M.P., India

2 Department of Chemistry, Government Institute of Science, Nagpur, M.H., India

3 Department of Chemistry, Government Science College, Gadchiroli, M.H., India

© 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,

4 Department of Chemistry, R.T.M., Nagpur University, Nagpur, M.H., India

, Satish S. Kola<sup>3</sup> and Rajendra S. Dongre<sup>4</sup>

Activity of Some 1-(20 ,30 -Dimethyl-10 - Phenyl-30 -Pyrazoline-50 -One-40 -Yl)-2- Phenyl-4-(Substituted Benzylidine)-5- Imidazolinones. Oriental Journal of Chemistry. 2001;**17**:315

[18] Mistry RN, Desa KR. Studies on synthesis of some novel heterocyclic azlactone derivatives and imidazolinone derivatives and their antimicrobial activity. E-Journal of Chemistry. 2005;**2**:42

[19] Kathrotiya HG, Patel NA, Patel RG, Patel MP. An efficient synthesis of 30 quinolinyl substituted imidazole-5-one derivatives catalyzed by zeolite and their antimicrobial activity. Chinese Chemical Letters. 2012;**23**:273

[20] Desai NC, Maheta AS, Rajpara KM, Joshi VV, Vaghani HV. Green synthesis of novel quinoline based imidazole derivatives and evaluation of their antimicrobi alactivity. Journal of Saudi Chemical Society. 2018;**14**:963

[21] Mohammad I, Bodkhe YG, Siddiqui NJ. Synthesis of some novel 5-imidazolones and its antimicrobial activity. International Research Journal of Pharmacy. 2018;**9**:85

[22] Khan KM, Mughal UR, Khan S, Khan S, Perveen S, Choudhary MI. Synthesis and antibacterial and antifungal activity of 5-substituted imidazolones. Letters in Drug Design and Discovery. 2009;**6**:69

[23] Andreani A, Locatelli AY, Rambaldi M. Synthesis and herbicidal properties of 3-(2-oxo-1-imidazolidinyliminomethyl) indoles; Journal of Heterocyclic Chemistry. 1995;**32**:49-51

[24] Zhou Y, Li Y, Zhu J, Lv J, Li Y, Zheng C, et al. Faming Zhuanli Shenqing Gongkai Shuoming shu. Patent CN 101691357 A 20100407; 2010

[25] Pai A, Singla RK, Joseph A, Kedar T, Thomas AT. Synthesis, in vitro and in

vivo anticancer activity of substituted imidazolones. Pharmacology. 2009;**2**:933

[34] Siddiqui NJ, Idrees M, Khati N, Dhonde M. Use of transesterified 1,3 diketoesters in the synthesis of trisubstituted pyrazoles and their biological screening. Bulletin of the Chemical Society of Ethiopia. 2013;**27**:85

*DOI: http://dx.doi.org/10.5772/intechopen.81269*

*Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium*

[35] Bauer AW, Kirby WM, Sherris JC, Turck M. Antibiotic susceptibility testing by a standardized single disk method. American Journal of Clinical

Pathology. 1966;**36**:493

**169**

[26] Shah MD, Desai NC, Awasthi KK, Saxena AK. Synthesis and QSAR studies of 5-imidazolinone derivatives as potential antibacterial agent. Indian Journal of Chemistry. 2001;**40**:201

[27] Patel PS, Shah RA, Trivedi DK, Vyas P. Synthesis and characterization of 4-{4-(2-methyl-4-benzylidene-5-oxoimidazol-1-yl)phenyl}-6 substitutedphenyl)-5,6 dihydropyrimi din -2-one and study of their antimicrobial actvities. Journal of Organic Chemistry: An Indian Journal. 2010;**6**:66

[28] Rao SN. Tracking binding modes of 1,2,4-trisubstituted imidazolinone P38 MAP kinase and ERK-2 inhibitors, Journal of Molecular Graphics & Modeling. 2017;**76**:161

[29] Xue N, Yang X, Wu R, Chen J, He Q, Yang B, Lu X, Hu Y. Synthesis and biological evaluation of imidazol-2-one derivatives as potential antitumor agents. Bioorganic & Medicinal Chemistry. 2008;**16**:2550

[30] Kagthara P, Shah N, Doshi R, Parekh H. Synthesis of some arylamides, sulphonamides and 5-oxo-imidazolines as novel bioactive compounds derived from benzimidazole. Heterocyclic Communications. 1998;**4**:6

[31] Knjariya H, Verma D, Parekh H. Oriental Journal of Chemistry. 2002;**18**: 583

[32] Acharya HH. Discovering the new heterocycles of therapeutic interest [PhD thesis]. Saurashtra University; 2004

[33] Furniss BS, Hanna Ford AJ, Smith PWG, Tatchell AR. Vogel's Text Book of Practical Organic Chemistry. 5th ed. ELBS; 1989

*Potent Antibacterial Profile of 5-Oxo-Imidazolines in the New Millennium DOI: http://dx.doi.org/10.5772/intechopen.81269*

[34] Siddiqui NJ, Idrees M, Khati N, Dhonde M. Use of transesterified 1,3 diketoesters in the synthesis of trisubstituted pyrazoles and their biological screening. Bulletin of the Chemical Society of Ethiopia. 2013;**27**:85

Activity of Some 1-(20

Chemistry. 2001;**17**:315


Phenyl-4-(Substituted Benzylidine)-5- Imidazolinones. Oriental Journal of

*Heterocycles - Synthesis and Biological Activities*

[18] Mistry RN, Desa KR. Studies on synthesis of some novel heterocyclic azlactone derivatives and imidazolinone derivatives and their antimicrobial activity. E-Journal of Chemistry.

[19] Kathrotiya HG, Patel NA, Patel RG, Patel MP. An efficient synthesis of 30

quinolinyl substituted imidazole-5-one derivatives catalyzed by zeolite and their antimicrobial activity. Chinese Chemical Letters. 2012;**23**:273

[20] Desai NC, Maheta AS, Rajpara KM, Joshi VV, Vaghani HV. Green synthesis of novel quinoline based imidazole derivatives and evaluation of their antimicrobi alactivity. Journal of Saudi

Chemical Society. 2018;**14**:963

[21] Mohammad I, Bodkhe YG, Siddiqui NJ. Synthesis of some novel 5-imidazolones and its antimicrobial activity. International Research Journal

[22] Khan KM, Mughal UR, Khan S, Khan S, Perveen S, Choudhary MI. Synthesis and antibacterial and antifungal activity of 5-substituted imidazolones. Letters in Drug Design

[23] Andreani A, Locatelli AY, Rambaldi M. Synthesis and herbicidal properties of 3-(2-oxo-1-imidazolidinyliminomethyl)

of Pharmacy. 2018;**9**:85

and Discovery. 2009;**6**:69

indoles; Journal of Heterocyclic Chemistry. 1995;**32**:49-51

**168**

[24] Zhou Y, Li Y, Zhu J, Lv J, Li Y, Zheng C, et al. Faming Zhuanli Shenqing Gongkai Shuoming shu. Patent CN 101691357 A 20100407; 2010

[25] Pai A, Singla RK, Joseph A, Kedar T, Thomas AT. Synthesis, in vitro and in

Phenyl-30

2005;**2**:42

,30




vivo anticancer activity of substituted imidazolones. Pharmacology. 2009;**2**:933

[26] Shah MD, Desai NC, Awasthi KK, Saxena AK. Synthesis and QSAR studies of 5-imidazolinone derivatives as potential antibacterial agent. Indian Journal of Chemistry. 2001;**40**:201

[27] Patel PS, Shah RA, Trivedi DK, Vyas P. Synthesis and characterization of 4-{4-(2-methyl-4-benzylidene-5-oxo-

substitutedphenyl)-5,6 dihydropyrimi

[28] Rao SN. Tracking binding modes of 1,2,4-trisubstituted imidazolinone P38 MAP kinase and ERK-2 inhibitors, Journal of Molecular Graphics &

[29] Xue N, Yang X, Wu R, Chen J, He Q, Yang B, Lu X, Hu Y. Synthesis and biological evaluation of imidazol-2-one derivatives as potential antitumor agents. Bioorganic & Medicinal Chemistry. 2008;**16**:2550

[30] Kagthara P, Shah N, Doshi R, Parekh H. Synthesis of some arylamides, sulphonamides and 5-oxo-imidazolines as novel bioactive compounds derived from benzimidazole. Heterocyclic Communications. 1998;**4**:6

[31] Knjariya H, Verma D, Parekh H. Oriental Journal of Chemistry. 2002;**18**:

[32] Acharya HH. Discovering the new heterocycles of therapeutic interest [PhD thesis]. Saurashtra University;

[33] Furniss BS, Hanna Ford AJ, Smith PWG, Tatchell AR. Vogel's Text Book of Practical Organic Chemistry. 5th ed.

imidazol-1-yl)phenyl}-6-

Modeling. 2017;**76**:161

2010;**6**:66

583

2004

ELBS; 1989

din -2-one and study of their antimicrobial actvities. Journal of Organic Chemistry: An Indian Journal.



[35] Bauer AW, Kirby WM, Sherris JC, Turck M. Antibiotic susceptibility testing by a standardized single disk method. American Journal of Clinical Pathology. 1966;**36**:493

**Chapter 12**

Agents

**Abstract**

**1. Introduction**

(4), tetrazole (5) and pentazole (6).

and 1,3,4-oxadiazole (18).

**171**

*Rohit Singh and Swastika Ganguly*

**Keywords:** imidazole, antibacterial, antifungal and antiviral

Azoles as Potent Antimicrobial

Imidazole analogs have proved to be a very good source of medicinal agents. The various activities associated with these moieties include antibacterial, antifungal, anthelmintic, Anti HIV activity, anticancer, antihypertensive, analgesic, anti-inflammatory, anticonvulsant, sedative and other pharmacological activities.

Azoles are basically five member heterocyclic compounds containing one or more different hetero atom out of which at least one must be nitrogen and other heterocyclic may be nitrogen or other than nitrogen like sulfur or oxygen.

Some of the common five member azoles which consist the nitrogen hetero atom only are as follows as imidazole (1), pyrazole (2), 1,2,3-triazole (3), 1,2,4-triazole

Some of the five member azoles which consist sulfur and oxygen as hetero atom along with nitrogen atom such as thiazole (7), isothiazole (8), 1,2,3-thiadiazole (9), 1,2,4-thiadiazole (10), 1,2,5-thiadiazole (11), 1,3,4-thiadiazole (12), oxazole (13), isoxazole (14), 1,2,3-oxadiazole (15), 1,2,4-oxadiazole (16), 1,2,5-oxadiazole (17)

#### **Chapter 12**

## Azoles as Potent Antimicrobial Agents

*Rohit Singh and Swastika Ganguly*

#### **Abstract**

Imidazole analogs have proved to be a very good source of medicinal agents. The various activities associated with these moieties include antibacterial, antifungal, anthelmintic, Anti HIV activity, anticancer, antihypertensive, analgesic, anti-inflammatory, anticonvulsant, sedative and other pharmacological activities.

**Keywords:** imidazole, antibacterial, antifungal and antiviral

#### **1. Introduction**

Azoles are basically five member heterocyclic compounds containing one or more different hetero atom out of which at least one must be nitrogen and other heterocyclic may be nitrogen or other than nitrogen like sulfur or oxygen.

Some of the common five member azoles which consist the nitrogen hetero atom only are as follows as imidazole (1), pyrazole (2), 1,2,3-triazole (3), 1,2,4-triazole (4), tetrazole (5) and pentazole (6).

Some of the five member azoles which consist sulfur and oxygen as hetero atom along with nitrogen atom such as thiazole (7), isothiazole (8), 1,2,3-thiadiazole (9), 1,2,4-thiadiazole (10), 1,2,5-thiadiazole (11), 1,3,4-thiadiazole (12), oxazole (13), isoxazole (14), 1,2,3-oxadiazole (15), 1,2,4-oxadiazole (16), 1,2,5-oxadiazole (17) and 1,3,4-oxadiazole (18).

Some of the heterocyclic azoles are fused with benzene ring to form bicyclic azole derivatives such as benzimidazole (19), benzotriazole (20), benzothiazole (21) and benzoxazole (22).

Giraldi et al. [15] in year 1967, synthesized a series of 1-aminoalkyl and 1 aminoalkyl-2-methyl-5(4)-nitro-4(5)-styrylimidazoles (30–37) and these compounds were tested to check the potency of synthesized compounds against various

*In vitro* activity against *Trichomonas vaginalis* of the compounds was found to be very potential, moderate against *Entamoeba histolytica* and least active against *Candida albicans.* It was found that those 5-nitroimidazoles in which the fourth position is free showed higher activity against *Trichomonas vaginalis*, whereas substituents at imidazole follow the order pyrrolidine > piperidine > diethylamine

In the year 1969, Lancini et al. [16] synthesized a various number of 1,5-disubstituted 2-nitro imidazoles (38–44) through diazotization reaction or Gattermann

All the synthesized compounds showed moderate *In vitro* activity against

Miller et al. [17] in the year 1970, synthesized a novel series of 2-methyl-5 nitroimidazoles (45–49) and evaluated their antiprotozoal activity. This series bore an aliphatic side chain incorporated with electronegative group. *In vitro* and *In vivo* evaluations were carried out against *Trichomonas foetus* and *Trichomonas vaginalis* as

non-pathogenic bacteria and fungi.

*Azoles as Potent Antimicrobial Agents*

*DOI: http://dx.doi.org/10.5772/intechopen.88547*

> morpholine.

*Trichomonas vaginalis.*

**173**

well as against *Entamoeba histolytica.*

reaction.

Among above mentioned class of azoles a brief review is presented focused on imidazoles and benzotriazoles as given below.

#### **2. Imidazole analogs and their significance**

In various oxidation states (23 and 24) imidazole has shown a number of interesting biological activities, like antiviral [1, 2], antibacterial [3] antifungal [4, 5], antiprotozoal [6, 7], antihypertensive [8, 9], antihistaminic [10], alpha-adrenergic agonist [11], alpha adrenergic blocking [12] and other activities [13, 14].

#### **2.1 Antiprotozoals**

Nitroimidazoles (25) with antitrichomonas activity were reported in year 1961 and then in 1966. Metronidazole (26) was among these compounds, it exhibited broad antiprotozoal activity and has found wide use in treating trichomoniasis orally.

Structural variation of Metronidazole (26), mainly to improve trichomonacidal activity led to the discovery of Tinidazole (27), Nimorazole (28), and Panidazole (29). Tinadazole (27) is most potent towards *Entamoeba histolytica*, *in vitro*, cecal amoebiasis and hepatic amoebiasis in experimental animals [6–8].

Some of the heterocyclic azoles are fused with benzene ring to form bicyclic azole derivatives such as benzimidazole (19), benzotriazole (20), benzothiazole

Among above mentioned class of azoles a brief review is presented focused on

In various oxidation states (23 and 24) imidazole has shown a number of interesting biological activities, like antiviral [1, 2], antibacterial [3] antifungal [4, 5], antiprotozoal [6, 7], antihypertensive [8, 9], antihistaminic [10], alpha-adrenergic

Nitroimidazoles (25) with antitrichomonas activity were reported in year 1961 and then in 1966. Metronidazole (26) was among these compounds, it exhibited broad antiprotozoal activity and has found wide use in treating trichomoniasis orally.

Structural variation of Metronidazole (26), mainly to improve trichomonacidal activity led to the discovery of Tinidazole (27), Nimorazole (28), and Panidazole (29). Tinadazole (27) is most potent towards *Entamoeba histolytica*, *in vitro*, cecal

amoebiasis and hepatic amoebiasis in experimental animals [6–8].

agonist [11], alpha adrenergic blocking [12] and other activities [13, 14].

(21) and benzoxazole (22).

**2.1 Antiprotozoals**

**172**

imidazoles and benzotriazoles as given below.

*Heterocycles - Synthesis and Biological Activities*

**2. Imidazole analogs and their significance**

Giraldi et al. [15] in year 1967, synthesized a series of 1-aminoalkyl and 1 aminoalkyl-2-methyl-5(4)-nitro-4(5)-styrylimidazoles (30–37) and these compounds were tested to check the potency of synthesized compounds against various non-pathogenic bacteria and fungi.

*In vitro* activity against *Trichomonas vaginalis* of the compounds was found to be very potential, moderate against *Entamoeba histolytica* and least active against *Candida albicans.* It was found that those 5-nitroimidazoles in which the fourth position is free showed higher activity against *Trichomonas vaginalis*, whereas substituents at imidazole follow the order pyrrolidine > piperidine > diethylamine > morpholine.

In the year 1969, Lancini et al. [16] synthesized a various number of 1,5-disubstituted 2-nitro imidazoles (38–44) through diazotization reaction or Gattermann reaction.


All the synthesized compounds showed moderate *In vitro* activity against *Trichomonas vaginalis.*

Miller et al. [17] in the year 1970, synthesized a novel series of 2-methyl-5 nitroimidazoles (45–49) and evaluated their antiprotozoal activity. This series bore an aliphatic side chain incorporated with electronegative group. *In vitro* and *In vivo* evaluations were carried out against *Trichomonas foetus* and *Trichomonas vaginalis* as well as against *Entamoeba histolytica.*

All compounds exhibited better activity against *Leishmania major* (IC50

alkyl/aryl imidazoles (73–91) and estimated their activity against *Leishmania*

Bhandari et al. [21] in the year 2010, synthesized a series of various substituted

Most of the synthesized compounds exhibited very significant activity up to 84–91% inhibition at the concentration of 10 μg/ml while some compounds showed

Hernandez-Nunez et al. [22] in the year 2009, reported synthesis of novel imidazole derivatives (103–117). These compounds were biologically examined against various parasites namely *Giardia intestinalis*,*Trichomonas vaginalis* and

Compounds (100–106) exhibited two fold better activity in comparison to benzimidazole analogs against *Trichomonas* vaginalis and *Giardia intestinalis* and

During the last 30 years, antifungal azoles [23] such as clotrimazole (107), miconazole (108), ketoconazole (109), butoconazole (110), econazole (111), cloconazole (112), fenticonazole (113), oxiconazole (114) and sulcoconazole (115)

found to be more active analogs against *Entamoeba histolytica*.

**2.2 Antibacterial and antifungal agents**

**175**

high IC50 values ranging from 0.47–4.85 μg/ml against amastigotes.

< 1.744 μM).

*Entamoeba histolytica*.

*donovani* as antileishmanial agents.

*Azoles as Potent Antimicrobial Agents*

*DOI: http://dx.doi.org/10.5772/intechopen.88547*

All the synthesized compounds showed mild activity against *Entamoeba histolytica* when compared to standard Tinidazole (27).

Nair et al. [18] in the year 1982, performed an acrylation of 1-methyl-5 nitroimidazole (50–58) with aroyl chlorides to form 2-aroyl-1-methyl-5 nitroimidazole through Beckmann rearrangement and yielded corresponding oximes and anilides as Beckmann product.

Walsh et al. [19] in the year 1986, synthesized a library of 5-nitroimidazole derivatives (59–65) which had ability to cause mutagenicity and these were also evaluated for their antitrichomonal activity.

Compounds 64 and 65 showed very less mutagenicity in comparison to standard drug ronidazole.

Foroumadi et al. [20] in the year 2005, synthesized a series of 2-(1-methyl-5-nitro imidazol-2-yl)-5-(1-piperazinyl, 1-piperidinyl and 1-morpholinyl)-1,3,4-thiadiazoles and estimated the antileishmanicidal activity for the synthesized compounds (77–83).

*Azoles as Potent Antimicrobial Agents DOI: http://dx.doi.org/10.5772/intechopen.88547*

All compounds exhibited better activity against *Leishmania major* (IC50 < 1.744 μM).

Bhandari et al. [21] in the year 2010, synthesized a series of various substituted alkyl/aryl imidazoles (73–91) and estimated their activity against *Leishmania donovani* as antileishmanial agents.

Most of the synthesized compounds exhibited very significant activity up to 84–91% inhibition at the concentration of 10 μg/ml while some compounds showed high IC50 values ranging from 0.47–4.85 μg/ml against amastigotes.

Hernandez-Nunez et al. [22] in the year 2009, reported synthesis of novel imidazole derivatives (103–117). These compounds were biologically examined against various parasites namely *Giardia intestinalis*,*Trichomonas vaginalis* and *Entamoeba histolytica*.

Compounds (100–106) exhibited two fold better activity in comparison to benzimidazole analogs against *Trichomonas* vaginalis and *Giardia intestinalis* and found to be more active analogs against *Entamoeba histolytica*.

#### **2.2 Antibacterial and antifungal agents**

During the last 30 years, antifungal azoles [23] such as clotrimazole (107), miconazole (108), ketoconazole (109), butoconazole (110), econazole (111), cloconazole (112), fenticonazole (113), oxiconazole (114) and sulcoconazole (115)

All the synthesized compounds showed mild activity against *Entamoeba*

Nair et al. [18] in the year 1982, performed an acrylation of 1-methyl-5 nitroimidazole (50–58) with aroyl chlorides to form 2-aroyl-1-methyl-5 nitroimidazole through Beckmann rearrangement and yielded corresponding

Walsh et al. [19] in the year 1986, synthesized a library of 5-nitroimidazole derivatives (59–65) which had ability to cause mutagenicity and these were also

Compounds 64 and 65 showed very less mutagenicity in comparison to standard

Foroumadi et al. [20] in the year 2005, synthesized a series of 2-(1-methyl-5-nitro imidazol-2-yl)-5-(1-piperazinyl, 1-piperidinyl and 1-morpholinyl)-1,3,4-thiadiazoles and estimated the antileishmanicidal activity for the synthesized compounds (77–83).

*histolytica* when compared to standard Tinidazole (27).

oximes and anilides as Beckmann product.

*Heterocycles - Synthesis and Biological Activities*

evaluated for their antitrichomonal activity.

drug ronidazole.

**174**

have been introduced. In all these compounds N-1 atom of imidazole is linked to other aromatic rings. The other antimycotic azoles have a five membered ring with three nitrogen atoms.

Sulphonidazole (116–117) showed better activity than sulphuridazole (118–119)

Demirayak et al. [25] in the year 1999, synthesized a novel series of some pyrrole-nitroimidazole clubbed hybrid derivatives (120–125) and evaluated their

Compounds 120–124 showed excellent activity against *Staphylococcus aureus* at the dose of 8 mg/ml while all the synthesized compounds exhibited excellent

Kolavi et al. [26] in the year 2006, synthesized a library of some imidazo thiadiazole derivatives (126–161) and evaluated their antibacterial activity.

against all the bacterial and fungal strains.

*DOI: http://dx.doi.org/10.5772/intechopen.88547*

*Azoles as Potent Antimicrobial Agents*

activity against fungal strain *Candida albicans*.

antifungal activity.

**177**

The antifungal azoles inhibit the cytochrome P-450 which catalyzes the 14-αdemethylation of lanosterol to ergosterol [15]. The azole drugs are relatively of broad spectrum antifungal activity but there may be differences among the individual compounds.

Castelli et al. [24] in the year 1997, synthesized two new compounds belonging to 5-nitroimidazole family: sulphuridazole and sulphonidazole derivatives (116–119) and compared their minimum inhibitory concentrations with metronidazole (26).

have been introduced. In all these compounds N-1 atom of imidazole is linked to other aromatic rings. The other antimycotic azoles have a five membered ring with

The antifungal azoles inhibit the cytochrome P-450 which catalyzes the 14-αdemethylation of lanosterol to ergosterol [15]. The azole drugs are relatively of broad spectrum antifungal activity but there may be differences among the indi-

Castelli et al. [24] in the year 1997, synthesized two new compounds belonging to 5-nitroimidazole family: sulphuridazole and sulphonidazole derivatives (116–119) and compared their minimum inhibitory concentrations with metronidazole (26).

three nitrogen atoms.

*Heterocycles - Synthesis and Biological Activities*

vidual compounds.

**176**

Sulphonidazole (116–117) showed better activity than sulphuridazole (118–119) against all the bacterial and fungal strains.

Demirayak et al. [25] in the year 1999, synthesized a novel series of some pyrrole-nitroimidazole clubbed hybrid derivatives (120–125) and evaluated their antifungal activity.

Compounds 120–124 showed excellent activity against *Staphylococcus aureus* at the dose of 8 mg/ml while all the synthesized compounds exhibited excellent activity against fungal strain *Candida albicans*.

Kolavi et al. [26] in the year 2006, synthesized a library of some imidazo thiadiazole derivatives (126–161) and evaluated their antibacterial activity.

The antibacterial screening revealed that compounds 134 and 140 showed significant activity against *Escherichia coli*. Compounds 126 and 127 showed good inhibition of *Escherichia coli* at a concentration of 100 μg/ml.

The antifungal screening revealed that the compounds 132, 134, 142, 159 and 161, displayed good antifungal activity against *Penicillium wortmannii* and *Aspergillus niger*.

Banfi et al. [27] in the year 2006 synthesized and evaluated new imidazoles (162–166) and (167–171) for antifungal and antimycobacterial activity.

The results showed that the compounds 166 and 171 showed very good activity, while rest of the derivatives exhibited weak antifungal activity against *Candida* species.

Compound (176) exhibited good activity against *Staphylococcus aureus* whereas compound (178) showed moderate activity towards *Escherichia coli*. However, all the compounds were less active than standard drug ciprofloxacin (184). Compounds (174) and (179) exhibited significant antifungal activities against *Candida albicans* comparable to the standard drug fluconazole (185). None of the com-

Sharma et al. [30] in the year 2009, synthesized a series of novel 2-substituted benzimidazoles (186–189) and imidazoles (190–193) from long chain alkenoic acids

pounds had appreciable anti-HIV activity.

*Azoles as Potent Antimicrobial Agents*

*DOI: http://dx.doi.org/10.5772/intechopen.88547*

**179**

and these were evaluated as antibacterial agents.

Mamolo et al. [28] in the year 2007, reported the synthesis of novel bisimidazole derivatives (172–175) and screened their antimycobacterial and antifungal activity.

Maximum compounds exhibited weak activity towards *Mycobacterium tuberculosis* and *Candida* species. Compound 175 was considered to be a significant antifungal agent against *Candida* species.

Ganguly et al. [29] in the year 2009, synthesized a few compounds of the type (176–183) and these were evaluated for antibacterial, antifungal and anti-HIV activity.

*Azoles as Potent Antimicrobial Agents DOI: http://dx.doi.org/10.5772/intechopen.88547*

The antibacterial screening revealed that compounds 134 and 140 showed significant activity against *Escherichia coli*. Compounds 126 and 127 showed

The antifungal screening revealed that the compounds 132, 134, 142, 159 and 161, displayed good antifungal activity against *Penicillium wortmannii* and

Banfi et al. [27] in the year 2006 synthesized and evaluated new imidazoles

The results showed that the compounds 166 and 171 showed very good activity, while rest of the derivatives exhibited weak antifungal activity against *Candida*

Maximum compounds exhibited weak activity towards *Mycobacterium tuberculosis* and *Candida* species. Compound 175 was considered to be a significant anti-

Ganguly et al. [29] in the year 2009, synthesized a few compounds of the type (176–183) and these were evaluated for antibacterial, antifungal and anti-HIV activity.

Mamolo et al. [28] in the year 2007, reported the synthesis of novel bisimidazole derivatives (172–175) and screened their antimycobacterial and

good inhibition of *Escherichia coli* at a concentration of 100 μg/ml.

*Heterocycles - Synthesis and Biological Activities*

(162–166) and (167–171) for antifungal and antimycobacterial activity.

*Aspergillus niger*.

species.

**178**

antifungal activity.

fungal agent against *Candida* species.

Compound (176) exhibited good activity against *Staphylococcus aureus* whereas compound (178) showed moderate activity towards *Escherichia coli*. However, all the compounds were less active than standard drug ciprofloxacin (184). Compounds (174) and (179) exhibited significant antifungal activities against *Candida albicans* comparable to the standard drug fluconazole (185). None of the compounds had appreciable anti-HIV activity.

Sharma et al. [30] in the year 2009, synthesized a series of novel 2-substituted benzimidazoles (186–189) and imidazoles (190–193) from long chain alkenoic acids and these were evaluated as antibacterial agents.

Compounds (190) and (193) were found to be most active against *Escherichia coli* and *Bacillus subtilis*. Whereas the imidazoles (186–189) exhibited moderate activity against the tested bacterial strains when compared to chloramphenicol (194) as standard.

Wu-Li-Ji et al. [31] in the year 2010, reported the synthesis of 2-benzyl thioimidazoles and 2-benzylthio sulfonyl-1H-imidazoles (195–208) and were evaluated for antibacterial, antifungal and antioxidant activity.


All newly reported derivatives exhibited excellent antibacterial activity towards *Proteus vulgaris* and *Klebsiella pneumonia* while exhibiting excellent antifungal activity towards *Penicillium chrysogenum.*

> Compounds 212, 215 and 220 exhibited moderate activity as antibacterials, however compounds 212, 213 and 215 showed weak anti-HIV activity as compared

> Ganguly et al. [34] in the year 2011 synthesized a few compounds of type (226–232) these were evaluated for antibacterial, antifungal and anti-HIV activity.

Compounds 228 exhibited 44% inhibitory activity against HIV-1 RT. Pathan and Rahatgoankar [35] in the year 2011, synthesized a series of

substituted 4,5-diphenyl imidazolyl-pyrimidine hybrids (233–239).

to the standard efavirenz (226).

*Azoles as Potent Antimicrobial Agents*

*DOI: http://dx.doi.org/10.5772/intechopen.88547*

**181**

Ganguly et al. [32] in the year 2010, synthesized some novel 2-methyl-5 nitroimidazole analogs (209–211). These were evaluated for antibacterial, antifungal and antidiarrheal activities.

Compounds 209–211 showed significant anti-diarrheal activity at a dose of 60 mg/kg body wt. while compound 209 exhibited significant antibacterial activity against *Staphylococcus aureus.*

Ganguly et al. [33] in the year 2011, reported some novel imidazole analogs of the type (261–274) and evaluated their antibacterial and anti-HIV activity.

*Azoles as Potent Antimicrobial Agents DOI: http://dx.doi.org/10.5772/intechopen.88547*

Compounds (190) and (193) were found to be most active against *Escherichia coli* and *Bacillus subtilis*. Whereas the imidazoles (186–189) exhibited moderate activity against the tested bacterial strains when compared to chloramphenicol

All newly reported derivatives exhibited excellent antibacterial activity towards

*Proteus vulgaris* and *Klebsiella pneumonia* while exhibiting excellent antifungal

Ganguly et al. [32] in the year 2010, synthesized some novel 2-methyl-5 nitroimidazole analogs (209–211). These were evaluated for antibacterial,

Compounds 209–211 showed significant anti-diarrheal activity at a dose of 60 mg/kg body wt. while compound 209 exhibited significant antibacterial activity

the type (261–274) and evaluated their antibacterial and anti-HIV activity.

Ganguly et al. [33] in the year 2011, reported some novel imidazole analogs of

activity towards *Penicillium chrysogenum.*

antifungal and antidiarrheal activities.

against *Staphylococcus aureus.*

**180**

Wu-Li-Ji et al. [31] in the year 2010, reported the synthesis of 2-benzyl thioimidazoles and 2-benzylthio sulfonyl-1H-imidazoles (195–208) and were

evaluated for antibacterial, antifungal and antioxidant activity.

(194) as standard.

*Heterocycles - Synthesis and Biological Activities*

Compounds 212, 215 and 220 exhibited moderate activity as antibacterials, however compounds 212, 213 and 215 showed weak anti-HIV activity as compared to the standard efavirenz (226).

Ganguly et al. [34] in the year 2011 synthesized a few compounds of type (226–232) these were evaluated for antibacterial, antifungal and anti-HIV activity.

Compounds 228 exhibited 44% inhibitory activity against HIV-1 RT. Pathan and Rahatgoankar [35] in the year 2011, synthesized a series of substituted 4,5-diphenyl imidazolyl-pyrimidine hybrids (233–239).

Vijesh et al. [37] in the year 2011, synthesized a dual series containing imidazole-

Among the tested compounds, compound 253 emerged as highly active against

Zhu et al. [38] in year 2012 reported the design and synthesized oxadiazole

Compound 312 with MIC of 1.56–3.13 μg/ml and compound 313 with MIC of 1.56–6.25 μg/ml were the most potent inhibitors of FabH against *Escherichia coli.* Desai et al. [39] in year 2012 synthesized a series of imidazole analogs (265–269)

*Trychophyton rubrum* compared to standard fluconazole.

derivatives (263–264) and evaluated their antibacterial activity.

and reported their activity towards bacterial and fungal species.

**183**

pyrazole combined derivatives (249–262).

*DOI: http://dx.doi.org/10.5772/intechopen.88547*

*Azoles as Potent Antimicrobial Agents*


Compound 236 was found to be most active against *Staphylococcus aureus* among all tested compounds.

Zhang and Zhou [36] in the year 2011 reported the synthesis of naphthalimide derived azoles (240–248) as novel anti-microbial agents and evaluated their efficiency *in vitro* against bacteria and fungi.

It was found that compounds 246–248 with different alkyl linkers were synthesized selectively and gave antibacterial profiles, especially compounds 246 and 247 showed prominent activity against *Pseudomonas aeruginosa* being eight fold more efficient than chloromycin.

Vijesh et al. [37] in the year 2011, synthesized a dual series containing imidazolepyrazole combined derivatives (249–262).

Among the tested compounds, compound 253 emerged as highly active against *Trychophyton rubrum* compared to standard fluconazole.

Zhu et al. [38] in year 2012 reported the design and synthesized oxadiazole derivatives (263–264) and evaluated their antibacterial activity.

Compound 312 with MIC of 1.56–3.13 μg/ml and compound 313 with MIC of 1.56–6.25 μg/ml were the most potent inhibitors of FabH against *Escherichia coli.*

Desai et al. [39] in year 2012 synthesized a series of imidazole analogs (265–269) and reported their activity towards bacterial and fungal species.


Compound 236 was found to be most active against *Staphylococcus aureus* among

Zhang and Zhou [36] in the year 2011 reported the synthesis of naphthalimide

It was found that compounds 246–248 with different alkyl linkers were synthesized selectively and gave antibacterial profiles, especially compounds 246 and 247 showed prominent activity against *Pseudomonas aeruginosa* being eight fold more

derived azoles (240–248) as novel anti-microbial agents and evaluated their

all tested compounds.

efficient than chloromycin.

**182**

efficiency *in vitro* against bacteria and fungi.

*Heterocycles - Synthesis and Biological Activities*

Compounds (265–269) were evaluated against *Gram-positive bacteria* mainly *Staphylococcus aureus*, *Staphylococcus pyogenes* and Gram-negative *bacteria* mainly *Escherichia coli*, *Pseudomonas aeruginosa* and fungi.

It was observed that substitution at meta position facilitates better activity rather than substitution at *ortho* and *para* position. Fluorine at meta position exhibited

De Martino et al. [40] replaced one phenyl ring of 1-[2-diarylmethoxy] ethyl) 2-methyl-5-nitroimidazoles (DAMNIs) with heterocyclic rings, such as 2-thienyl (273) or 3-pyridinyl ring (274), leading to novel DAMNIs with increased activity.

N-Alkylation of imidazole, 2-methyl imidazole and 2-methyl-4-nitroimidazole

Among all synthesized compounds, 276, 279 and 282 exhibited very significant anti HIV-1 integrase inhibitory activity. Especially, compound 277 showed highest

Serrao et al. [42] in the year 2013, reported a novel series of 5-carbonyl-1Himidazole-4-carboxamides (283–299) capable of inhibiting HIV-1 integrase–

activity with EC50 value 7.88 μg/ml and therapeutic index 24.61.

LEDGF/p75 interaction.

**185**

Xu et al. [41] in the year 2008 synthesized some novel derivatives of Narylindoles (275–282) and evaluated as HIV integrase inhibitors for first time.

maximum potency among all derivatives.

*DOI: http://dx.doi.org/10.5772/intechopen.88547*

*Azoles as Potent Antimicrobial Agents*

has been carried to achieve effective antiHIV agents.

#### **2.3. Antiviral agents**

The first report on N-Amino imidazoles as antiHIV agents and particularly as NNRTIs came up with the discovery of Capravirine (S-1153) (270) in the year 2000 [1]. This also retained activity against HIV-1 strains carrying K103N mutation in RT structure.

After this, anti-viral active N-amino imidazole (271) derivatives were reported by Lagoja et al. [2] in the year 2003, which exhibited considerable antiviral activity.

Methylation or benzoylation on sulfur group may demolish the anti HIV activity of compound, whereas compounds bearing alkyl/aryl substituents at para position to imidazole ring affected the antiHIV activity. Smaller the substituent higher the activity.

Silvestri et al. [40] in the year 2002 synthesized a novel series of 1-{2- (diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles (272) and evaluated their antiHIV activity.

Substitution at meta position to the phenyl ring exhibited better anti-HIV activity while substituents like fluoro, chloro or methyl substituent enhances the activity than its prototype.

*Azoles as Potent Antimicrobial Agents DOI: http://dx.doi.org/10.5772/intechopen.88547*

Compounds (265–269) were evaluated against *Gram-positive bacteria* mainly *Staphylococcus aureus*, *Staphylococcus pyogenes* and Gram-negative *bacteria* mainly

The first report on N-Amino imidazoles as antiHIV agents and particularly as NNRTIs came up with the discovery of Capravirine (S-1153) (270) in the year 2000 [1]. This also retained activity against HIV-1 strains carrying K103N mutation in RT structure.

After this, anti-viral active N-amino imidazole (271) derivatives were reported by Lagoja et al. [2] in the year 2003, which exhibited considerable antiviral activity.

Methylation or benzoylation on sulfur group may demolish the anti HIV activity of compound, whereas compounds bearing alkyl/aryl substituents at para position to imidazole ring affected the antiHIV activity. Smaller the substituent higher the activity. Silvestri et al. [40] in the year 2002 synthesized a novel series of 1-{2- (diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles (272) and evaluated their

Substitution at meta position to the phenyl ring exhibited better anti-HIV activity while substituents like fluoro, chloro or methyl substituent enhances the activity

*Escherichia coli*, *Pseudomonas aeruginosa* and fungi.

*Heterocycles - Synthesis and Biological Activities*

**2.3. Antiviral agents**

antiHIV activity.

than its prototype.

**184**

It was observed that substitution at meta position facilitates better activity rather than substitution at *ortho* and *para* position. Fluorine at meta position exhibited maximum potency among all derivatives.

De Martino et al. [40] replaced one phenyl ring of 1-[2-diarylmethoxy] ethyl) 2-methyl-5-nitroimidazoles (DAMNIs) with heterocyclic rings, such as 2-thienyl (273) or 3-pyridinyl ring (274), leading to novel DAMNIs with increased activity.

N-Alkylation of imidazole, 2-methyl imidazole and 2-methyl-4-nitroimidazole has been carried to achieve effective antiHIV agents.

Xu et al. [41] in the year 2008 synthesized some novel derivatives of Narylindoles (275–282) and evaluated as HIV integrase inhibitors for first time.


Among all synthesized compounds, 276, 279 and 282 exhibited very significant anti HIV-1 integrase inhibitory activity. Especially, compound 277 showed highest activity with EC50 value 7.88 μg/ml and therapeutic index 24.61.

Serrao et al. [42] in the year 2013, reported a novel series of 5-carbonyl-1Himidazole-4-carboxamides (283–299) capable of inhibiting HIV-1 integrase– LEDGF/p75 interaction.

All the synthesized compounds showed almost equivalent activity as their MTT/ MT-4 (CC50 and EC50) values were same.

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Huang et al. [43] in the year 2017, synthesized a series of diarylpyrimidines (300–310) and indolylarylsulphones (311–321) hybrids and showed their activity against HIV1-IIIB strain.

Compound 311 exhibited favorable selectivity index (SI = 80) which was the maximum above all synthesized compounds and determined by MTT method.

#### **3. Conclusion**

Compounds containing azole derivatives, exhibit a wide variety of activities such as antibacterial, antifungal, anthelmintic, antiprotozoal, antiviral, anticancer, antihistaminic, antiulcer, antipsychotic and various other biological activities.

#### **Author details**

Rohit Singh\* and Swastika Ganguly Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India

\*Address all correspondence to: rohitsingh20485bitmesra@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.

*Azoles as Potent Antimicrobial Agents DOI: http://dx.doi.org/10.5772/intechopen.88547*

#### **References**

All the synthesized compounds showed almost equivalent activity as their MTT/

Huang et al. [43] in the year 2017, synthesized a series of diarylpyrimidines (300–310) and indolylarylsulphones (311–321) hybrids and showed their activity

Compound 311 exhibited favorable selectivity index (SI = 80) which was the maximum above all synthesized compounds and determined by MTT method.

Compounds containing azole derivatives, exhibit a wide variety of activities such as antibacterial, antifungal, anthelmintic, antiprotozoal, antiviral, anticancer, antihistaminic, antiulcer, antipsychotic and various other biological activities.

Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra,

© 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: rohitsingh20485bitmesra@gmail.com

MT-4 (CC50 and EC50) values were same.

*Heterocycles - Synthesis and Biological Activities*

against HIV1-IIIB strain.

**3. Conclusion**

**Author details**

**186**

Ranchi, Jharkhand, India

Rohit Singh\* and Swastika Ganguly

provided the original work is properly cited.

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(diarylmethoxy) ethyl]-2-methyl-5 nitroimidazoles targeted at the HIV-1 reverse transcriptase. Journal of Medicinal Chemistry. 2002;**45**(8):

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binding mode of novel 1-[2-

**21**(14):4349-4352

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[31] Wu-Li-Ji A, Qing-Hu W, Na-Yin-Tai D. The structural elucidation and antimicrobial activities of two new sesquiterpenes from Syringa pinnatifolia Hemsl. Chinese Journal of Natural Medicines. 2012;**10**(6):

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Synthesis, antibacterial and potential anti-HIV activity of some novel

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synthesis and evaluation of some 1- {2-(Hydroxyethyl)}-2-methyl-5 nitroimidazole analogs. Institution of

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[33] Ganguly S, Vithlani V, Kesharwani A, Kuhu R, Baskar L,

Dev A. Microwave assisted

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a new type of antibacterial and antifungal agents. Bioorganic &

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[25] Demirayak S, Karaburun AÇ, Kiraz N. Synthesis and antibacterial activities of some 1-[2-(substituted pyrrol-1-yl) ethyl]-2-methyl-5 nitroimidazole derivatives. European Journal of Medicinal Chemistry. 1999; **34**(3):275-278

[26] Kolavi G, Hegde V, ahmed Khazi I, Gadad P. Synthesis and evaluation of antitubercular activity of imidazo [2, 1 b][1, 3, 4] thiadiazole derivatives. Bioorganic & Medicinal Chemistry. 2006;**14**(9):3069-3080

[27] Banfi E, Scialino G, Zampieri D, Mamolo MG, Vio L, Ferrone M, et al. Antifungal and antimycobacterial activity of new imidazole and triazole derivatives. A combined experimental and computational approach. Journal of Antimicrobial Chemotherapy. 2006; **58**(1):76-84

[28] Zampieri D, Mamolo MG, Vio L, Banfi E, Scialino G, Fermeglia M, et al. Synthesis, antifungal and antimycobacterial activities of new bis-imidazole derivatives, and prediction of their binding to P45014DM by molecular docking and MM/PBSA method. Bioorganic & Medicinal Chemistry. 2007;**15**(23): 7444-7458

[29] Ganguly S, Gopalakrishnan V, Chandra R. Synthesis and antibacterial *Azoles as Potent Antimicrobial Agents DOI: http://dx.doi.org/10.5772/intechopen.88547*

activity of some new 1-substituted 2 methyl-4-nitroimidazoles. International Journal of Chemical Sciences. 2009;**7**: 204-210

2-nitroimidazole derivatives. Journal of Medicinal Chemistry. 1969;**12**(5):

*Heterocycles - Synthesis and Biological Activities*

nitro-1H-imidazoles. European Journal of Medicinal Chemistry. 2009;**44**(7):

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[24] Castelli M, Malagoli M, Ruberto A, Baggio A, Casolari C, Cermelli C, et al. In-vitro studies of two 5-nitroimidazole

Antimicrobial Chemotherapy. 1997;

[25] Demirayak S, Karaburun AÇ, Kiraz N. Synthesis and antibacterial activities of some 1-[2-(substituted pyrrol-1-yl) ethyl]-2-methyl-5 nitroimidazole derivatives. European Journal of Medicinal Chemistry. 1999;

[26] Kolavi G, Hegde V, ahmed Khazi I, Gadad P. Synthesis and evaluation of antitubercular activity of imidazo [2, 1 b][1, 3, 4] thiadiazole derivatives. Bioorganic & Medicinal Chemistry.

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[28] Zampieri D, Mamolo MG, Vio L, Banfi E, Scialino G, Fermeglia M, et al.

antimycobacterial activities of new bis-imidazole derivatives, and prediction of their binding to

P45014DM by molecular docking and MM/PBSA method. Bioorganic & Medicinal Chemistry. 2007;**15**(23):

[29] Ganguly S, Gopalakrishnan V, Chandra R. Synthesis and antibacterial

Synthesis, antifungal and

derivatives. The Journal of

2975-2984

Vol. 5

**40**(1):19-25

**34**(3):275-278

**58**(1):76-84

7444-7458

2006;**14**(9):3069-3080

Kasubick RV, English AR. Alkylation of 2-methyl-5-nitroimidazole. Some potent

[17] Miller MW, Howes HL Jr,

antiprotozoal agents. Journal of Medicinal Chemistry. 1970;**13**(5):

[18] Nair M, Sudarsanam V, Desai J. Nitroimidazoles. 12. Reaction of 1 methyl-5-nitroimidazoles with acid-chlorides. Indian Journal of Chemistry Section. 1982;**21**(11):

[19] Walsh JS, Wang R, Bagan E, Wang C, Wislocki P, Miwa GT.

affect the mutagenic and antitrichomonal activities of 5 nitroimidazoles. Journal of Medicinal Chemistry. 1987;**30**(1):150-156

[20] Foroumadi A, Emami S,

2-yl) piperazinyl quinolone

[21] Bhandari K, Srinivas N,

aryloxy alkyl and aryloxy aryl alkyl imidazoles as

4488-4492

**20**(1):291-293

**188**

Structural alterations that differentially

Hassanzadeh A, Rajaee M, Sokhanvar K, Moshafi MH, et al. Synthesis and antibacterial activity of N-(5-

benzylthio-1, 3, 4-thiadiazol-2-yl) and N-(5-benzylsulfonyl-1, 3, 4-thiadiazol-

derivatives. Bioorganic & Medicinal Chemistry Letters. 2005;**15**(20):

Marrapu VK, Verma A, Srivastava S, Gupta S. Synthesis of substituted

antileishmanial agents. Bioorganic & Medicinal Chemistry Letters. 2010;

[22] Hernández-Núñez E, Tlahuext H, Moo-Puc R, Torres-Gómez H, Reyes-Martínez R, Cedillo-Rivera R, et al. Synthesis and in vitro trichomonicidal, giardicidal and amebicidal activity of Nacetamide (sulfonamide)-2-methyl-4-

775-780

849-852

1027-1029

[30] Sharma S, Gangal S, Rauf A. Convenient one-pot synthesis of novel 2-substituted benzimidazoles, tetrahydrobenzimidazoles and imidazoles and evaluation of their in vitro antibacterial and antifungal activities. European Journal of Medicinal Chemistry. 2009;**44**(4): 1751-1757

[31] Wu-Li-Ji A, Qing-Hu W, Na-Yin-Tai D. The structural elucidation and antimicrobial activities of two new sesquiterpenes from Syringa pinnatifolia Hemsl. Chinese Journal of Natural Medicines. 2012;**10**(6): 477-480

[32] Ganguly S, Gupta PK, Dev A. Synthesis and antimicrobial evaluation of some 1-substituted 2-methyl-5 nitroimidazoles. Pharmbit. 2010;**21**(1): 29-32

[33] Ganguly S, Vithlani V, Kesharwani A, Kuhu R, Baskar L, Mitramazumder P, et al. Synthesis, antibacterial and potential anti-HIV activity of some novel imidazole analogs. Acta Pharmaceutica. 2011;**61**(2):187-201

[34] Ganguly S, Panigrahi N, Cremer SN, Dev A. Microwave assisted synthesis and evaluation of some 1- {2-(Hydroxyethyl)}-2-methyl-5 nitroimidazole analogs. Institution of Chemist India. 2011;**83**:65-71

[35] Pathan BN, Rahatgaonkar AM. Arabian Journal of Chemistry. 2011

[36] Zhang Y-Y, Zhou C-H. Synthesis and activities of naphthalimide azoles as a new type of antibacterial and antifungal agents. Bioorganic &

Medicinal Chemistry Letters. 2011; **21**(14):4349-4352

[37] Vijesh A, Isloor AM, Telkar S, Peethambar S, Rai S, Isloor N. Synthesis, characterization and antimicrobial studies of some new pyrazole incorporated imidazole derivatives. European Journal of Medicinal Chemistry. 2011;**46**(8):3531-3536

[38] Li Y, Luo Y, Hu Y, Zhu D-D, Zhang S, Liu Z-J, et al. Design, synthesis and antimicrobial activities of nitroimidazole derivatives containing 1, 3, 4-oxadiazole scaffold as FabH inhibitors. Bioorganic & Medicinal Chemistry. 2012;**20**(14):4316-4322

[39] Desai N, Joshi V, Rajpara K, Makwana AH. A new synthetic approach and in vitro antimicrobial evaluation of novel imidazole incorporated 4-thiazolidinone motifs. Arabian Journal of Chemistry. 2017;**10**: S589-S599

[40] Silvestri R, Artico M, De Martino G, Ragno R, Massa S, Loddo R, et al. Synthesis, biological evaluation, and binding mode of novel 1-[2- (diarylmethoxy) ethyl]-2-methyl-5 nitroimidazoles targeted at the HIV-1 reverse transcriptase. Journal of Medicinal Chemistry. 2002;**45**(8): 1567-1576

[41] Xu H, Liu W-Q, Fan L-L, Chen Y, Yang L-M, Lv L, et al. Synthesis and HIV-1 integrase inhibition activity of some N-arylindoles. Chemical and Pharmaceutical Bulletin. 2008;**56**(5): 720-722

[42] Serrao E, Xu Z-L, Debnath B, Christ F, Debyser Z, Long Y-Q, et al. Discovery of a novel 5-carbonyl-1Himidazole-4-carboxamide class of inhibitors of the HIV-1 integrase– LEDGF/p75 interaction. Bioorganic & Medicinal Chemistry. 2013;**21**(19): 5963-5972

*Heterocycles - Synthesis and Biological Activities*

[43] Huang B, Wang X, Liu X, Chen Z, Li W, Sun S, et al. Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays. Bioorganic & Medicinal Chemistry. 2017;**25**(16): 4397-4406

[43] Huang B, Wang X, Liu X, Chen Z, Li W, Sun S, et al. Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays. Bioorganic & Medicinal Chemistry. 2017;**25**(16):

*Heterocycles - Synthesis and Biological Activities*

4397-4406

**190**

### *Edited by B. P. Nandeshwarappa and Sadashiv S. O.*

Heterocycles have constituted the largest area of research in organic chemistry. These heterocycles play an important role in biochemical processes because the side groups of the most typical and essential constituents of living cells, DNA and RNA, are based on aromatic heterocycles. Many synthetic methods have been developed for the preparation of heterocycles. The recent surge of interest in the chemistry of heterocycles can be explained by their unusual properties and exotic structure. These heterocycles include highly stable aromatic compounds that display physicochemical properties with relevance in the design of new materials. Thus, heterocycles contribute to the development of society from a biological and industrial point of view.

Published in London, UK © 2020 IntechOpen © smirkdingo / iStock

Heterocycles - Synthesis and Biological Activities

Heterocycles

Synthesis and Biological Activities

*Edited by B. P. Nandeshwarappa and Sadashiv S. O.*