**2. Synthesis of quinazoline and quinazolinone derivatives**

1.Synthesis of 4(3H)-quinazolinone using anthranilic acid or formyl anthranilamide [24].

2.Via condensation reaction of 4-chloroanthranilic acid amide with triethyl orthoformate, the 7-chloro-substituted derivative has been prepared [25].

3.Quinazolin-4(3H)-one was synthesized by the reaction of anthranilic acid with excess formamide at 120°C in an open air. This is also known as Niementowski reaction [26].

4. 2-styryl-4(3H)-quinazolinone derivatives were prepared using starting substrate 2-aminobenzonitrile with 3-phenyl cinnamoyl chloride. Under alkaline conditions, intramolecular cyclization of cinnamamide derivative was carried out to afford 2-styryl-4(3H)-quinazolinone. This procedure was tolerated to a wide range of different substituted benzene rings [27].

*Quinazolinone and Quinazoline Derivatives*

**76**

**Figure 1.**

*Quinazoline and quinazolinone-based drugs.*

Several quinazolinone-based drugs including idelalisib and fenquizone have been shown to exhibit a broad spectrum of antimicrobial, antitumor, antifungal, and cytotoxic activities [20]. Lapatinib has been displayed to be effective in combination therapy for breast cancer [21]. In the recent years, various synthetic strategies for the synthesis of quinazolines and quinazolinones derivatives have

5.Reaction of anthranilic acid with ammonium acetate, followed by formamide under microwave at 200 W yields the desired 2-substituted-4(3H)-quinazolinones products [28].

6.Reaction of anthranilamide with substituted aldehydes or ketones in 2,2,2-trifluoroethanol under reflux condition led to the formation of 2-substituted-2,3-dihydro-4(1H)-quinazolinones in excellent yields [27].

7.The amino-quinazolin-4(3H)-one was synthesized by means of the reaction of the corresponding methyl anthranilate with an excess amount of guanidine in ethyl alcohol containing sodium ethoxide in moderate yield [29].

8.4-Arylaminoquinazolines has vast biological potential as anticancer agents, thus there has been great interest in their syntheses. Through the reaction of 2-aminobenzonitrile with different substituted anilines and anhydrous aluminum chloride, amidines were readily produced. Highest yield of the amidine intermediates was obtained, when excess amounts of suitable aniline and aluminum chloride were used [30].

9. 2,3-disubstituted-4(3H)-quinazolinone derivatives were prepared through the treatment of N-acylanthranilic acid with the appropriate aryl amines in the presence of phosphorous oxychloride [31].

**79**

*Quinazolinone and Quinazoline Derivatives: Synthesis and Biological Application*

acid with acetic anhydride in acetic acid [32].

10. Benzoxazinone derivatives are the most widespread intermediates in the formation of 2,3-disubstituted quinazolinone derivatives. 2-methyl-4Hbenzo[d][1,3]oxazin-4-one was prepared by refluxing mixture of anthranilic

11. The reaction of 2-aminobenzonitrile with Grignard reagents yields the intermediates. The produced intermediate derivatives were very significant for getting many types of quinazoline derivatives. Upon their cyclization with acid chlorides, anhydrides, and formates, they formed the corresponding quinazoline derivatives in moderate to good yields. This general method for the preparation of various 2,4-disubstituted quinazoline derivatives is highly

12. As shown in the scheme 2-chloromethyl-4-methyl-quinazoline derivatives were synthesized by the reaction 1-(2-amino-phenyl)-ethanone with HCl gas in anhydrous condition in presence of chloro acetonitrile to get 2-chloromethyl-4-methyl-quinazoline. Subsequently treatment of 2-chloromethyl-4-methyl-quinazoline with different amine derivative in presence of base

furnished 2-chloromethyl-4-methyl-quinazoline derivatives [34].

**3. Biological activities of quinazolinone and quinazoline derivatives**

Subsequently the innovation of quinazoline ring numeral of structural modifications have been made in order to raise the biological activities such as antitubercular,

*DOI: http://dx.doi.org/10.5772/intechopen.89203*

flexible and useful [33].

*Quinazolinone and Quinazoline Derivatives: Synthesis and Biological Application DOI: http://dx.doi.org/10.5772/intechopen.89203*

10. Benzoxazinone derivatives are the most widespread intermediates in the formation of 2,3-disubstituted quinazolinone derivatives. 2-methyl-4Hbenzo[d][1,3]oxazin-4-one was prepared by refluxing mixture of anthranilic acid with acetic anhydride in acetic acid [32].

11. The reaction of 2-aminobenzonitrile with Grignard reagents yields the intermediates. The produced intermediate derivatives were very significant for getting many types of quinazoline derivatives. Upon their cyclization with acid chlorides, anhydrides, and formates, they formed the corresponding quinazoline derivatives in moderate to good yields. This general method for the preparation of various 2,4-disubstituted quinazoline derivatives is highly flexible and useful [33].

12. As shown in the scheme 2-chloromethyl-4-methyl-quinazoline derivatives were synthesized by the reaction 1-(2-amino-phenyl)-ethanone with HCl gas in anhydrous condition in presence of chloro acetonitrile to get 2-chloromethyl-4-methyl-quinazoline. Subsequently treatment of 2-chloromethyl-4-methyl-quinazoline with different amine derivative in presence of base furnished 2-chloromethyl-4-methyl-quinazoline derivatives [34].

### **3. Biological activities of quinazolinone and quinazoline derivatives**

Subsequently the innovation of quinazoline ring numeral of structural modifications have been made in order to raise the biological activities such as antitubercular,

*Quinazolinone and Quinazoline Derivatives*

zolinones products [28].

5.Reaction of anthranilic acid with ammonium acetate, followed by formamide under microwave at 200 W yields the desired 2-substituted-4(3H)-quina-

6.Reaction of anthranilamide with substituted aldehydes or ketones in 2,2,2-trifluoroethanol under reflux condition led to the formation of 2-substituted-

7.The amino-quinazolin-4(3H)-one was synthesized by means of the reaction of the corresponding methyl anthranilate with an excess amount of guanidine in

8.4-Arylaminoquinazolines has vast biological potential as anticancer agents, thus there has been great interest in their syntheses. Through the reaction of 2-aminobenzonitrile with different substituted anilines and anhydrous aluminum chloride, amidines were readily produced. Highest yield of the amidine intermediates was obtained, when excess amounts of suitable aniline

9. 2,3-disubstituted-4(3H)-quinazolinone derivatives were prepared through the treatment of N-acylanthranilic acid with the appropriate aryl amines in the

ethyl alcohol containing sodium ethoxide in moderate yield [29].

and aluminum chloride were used [30].

presence of phosphorous oxychloride [31].

2,3-dihydro-4(1H)-quinazolinones in excellent yields [27].

**78**


#### **Figure 2.**

*Anticancer activities of quinazolinone and quinazoline derivatives.*

antihistaminic, analgesic, anticonvulsant, antibacterial, antifungal, and anti-inflammatory activity which attracted the interest of medicinal chemists.

Cancerous augmentation is the main reasons of global human mortality. Numerous antineoplastic drugs are in the market and the majority of the compounds are under

**81**

anti-inflammatory agents [58].

*Quinazolinone and Quinazoline Derivatives: Synthesis and Biological Application*

for their various anticancer activities (**Figure 2**) [35–56].

clinical trials. Studies make known that these antineoplastic drugs have exhibited the diverse kinds of side effects, as a result researchers around the world are engaged in the designing of more proficient and novel antineoplastic drugs. Recently, quinazoline and its derivatives have been considered as a novel class of neoplastic chemotherapeutic agents to facilitate activity against diverse tumors. Quinazoline is one of the most attractive novel bioactive compounds between all the heterocyclic compounds.

Quinazolinone derivatives, the privileged structures in the field of medicinal chemistry not only act as good anticancer agents but also act as good DNA intercalates [1, 2]. A systematic report is depicted herein for quinazoline ring. A number of quinazolinone and quinazoline derivatives (compounds **1**–**24**) have been reported

A series of quinazolinone derived Schiff base derivatives were synthesized and evaluated for their in vitro H+/K+-ATPase inhibition. Many quinazolinone derived Schiff base exhibited outstanding potency, compared to the reference drug omeprazole. Especially, hydroxy and methoxy derivatives were the most potent compounds, contributing positively to gastric H+/K+-ATPase inhibition. Preliminary structureactivity relationship revealed that the compounds **25**–**30** with electron donating moiety (OH, OCH3) were found to be excellent activity and compounds **31**–**34** with electron withdrawing moiety (Cl and NO2) were found to be least antiulcer agents [57].

Quinazolinone derived Schiff base derivatives were also used as novel antioxidants and anti-inflammatory agents. The in vitro antioxidant activities of these compounds were evaluated and compared with commercial antioxidants viz. ascorbic acid (AA), gallic acid (GA), butylated hydroxytoluene (BHT), (DPPH) assay, etc. Data illustrates that quinazolinone derived Schiff base with electron donating moiety (OH, OCH3) were found to be excellent antioxidants and compounds with electron withdrawing moiety (Cl, NO2) were found to be excellent

*DOI: http://dx.doi.org/10.5772/intechopen.89203*

*Quinazolinone and Quinazoline Derivatives: Synthesis and Biological Application DOI: http://dx.doi.org/10.5772/intechopen.89203*

clinical trials. Studies make known that these antineoplastic drugs have exhibited the diverse kinds of side effects, as a result researchers around the world are engaged in the designing of more proficient and novel antineoplastic drugs. Recently, quinazoline and its derivatives have been considered as a novel class of neoplastic chemotherapeutic agents to facilitate activity against diverse tumors. Quinazoline is one of the most attractive novel bioactive compounds between all the heterocyclic compounds.

Quinazolinone derivatives, the privileged structures in the field of medicinal chemistry not only act as good anticancer agents but also act as good DNA intercalates [1, 2]. A systematic report is depicted herein for quinazoline ring. A number of quinazolinone and quinazoline derivatives (compounds **1**–**24**) have been reported for their various anticancer activities (**Figure 2**) [35–56].

A series of quinazolinone derived Schiff base derivatives were synthesized and evaluated for their in vitro H+/K+-ATPase inhibition. Many quinazolinone derived Schiff base exhibited outstanding potency, compared to the reference drug omeprazole. Especially, hydroxy and methoxy derivatives were the most potent compounds, contributing positively to gastric H+/K+-ATPase inhibition. Preliminary structureactivity relationship revealed that the compounds **25**–**30** with electron donating moiety (OH, OCH3) were found to be excellent activity and compounds **31**–**34** with electron withdrawing moiety (Cl and NO2) were found to be least antiulcer agents [57].

Quinazolinone derived Schiff base derivatives were also used as novel antioxidants and anti-inflammatory agents. The in vitro antioxidant activities of these compounds were evaluated and compared with commercial antioxidants viz. ascorbic acid (AA), gallic acid (GA), butylated hydroxytoluene (BHT), (DPPH) assay, etc. Data illustrates that quinazolinone derived Schiff base with electron donating moiety (OH, OCH3) were found to be excellent antioxidants and compounds with electron withdrawing moiety (Cl, NO2) were found to be excellent anti-inflammatory agents [58].

*Quinazolinone and Quinazoline Derivatives*

**80**

**Figure 2.**

antihistaminic, analgesic, anticonvulsant, antibacterial, antifungal, and anti-inflam-

Cancerous augmentation is the main reasons of global human mortality. Numerous antineoplastic drugs are in the market and the majority of the compounds are under

matory activity which attracted the interest of medicinal chemists.

*Anticancer activities of quinazolinone and quinazoline derivatives.*

Plausible pathways induced by inhibitors were assessed by evaluating the cytotoxic effect of inhibitors such as 3-(5-chloro-2-hydroxybenzylideneamino)- 2-(5-chloro-2-hydroxyphenyl)-2,3-dihydroquinazolin-41(H)-one (**35**) and 3-(5-nitro-2-hydroxybenzylideneamino)-2-(5-nitro-2-hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (**36**) on MCF-7, MDA-MB-231, MCF-10A and WRL-68 cells. MTT assay results of both the compounds showed significant inhibition of MCF-7 cell viability [59].

Azaisatins derivative containing 4(3H) quinazolinones has been designed and synthesized and were screened for their potential antimicrobial activities, which exhibited some authentic results towards testing organism *in vitro* and *in vivo* studies. Azaisatins derivatives with –C6H13 (**40**) display good antimicrobial activity compare to other synthesized Azaisatins [60].

Quinazolinone derivatives containing 3-acrylamino motifs were screened for antifungal activities against four phytopathogenic fungi by minimum inhibitory concentration (MIC) method. Compounds **41**–**43**, exhibited broad antifungal activities and substituent's play important role in activities [61].

**83**

*Quinazolinone and Quinazoline Derivatives: Synthesis and Biological Application*

A series of novel quinazolinone derivatives containing an amino substituted amino moiety were reported for their cytotoxic and antibacterial activities. Among the synthesized compounds **47**–**49** showed broad-spectrum cytotoxic activities giants at least four cancer cell lines at low concentrations. Compounds **44**–**46** exhibited good to moderate antibacterial activities against gram positive and gram

Quinazolinone derivatives manipulate mutant p53 proteins and their corresponding cellular response in p53 mutant cancer cells. Compounds **50** and **51** exhibited promising broad-spectrum anti-cancer effects, while **50** demonstrated selective and exclusive inhibition activity in p53 mutant cancer cell lines. Quinazolinone

2-(4-bromophenyl)-quinazolin-4(3H)-one (**52A**) and 2-(4-chlorophenyl) quinazolin-4(3H)-one (**52B**) exhibited α-glucosidase inhibitory activity with IC50 values of 12.5 ± 0.1 lM and 15.6 ± 0.2 lM, respectively. Spectroscopy methods were performed to analyze the inhibitory mechanisms of both compounds on α-glucosidase. The outcome of inhibitory mechanism disclosed, that the compounds, inhibited α-glucosidase in reversible and non-competitive manner. Briefly, the quinazolinone derivatives could be potentially promising candidates in the field

RAD51 is an essential component of the homologous recombination DNA repair pathway and is over expressed in drug-resistant cancers, including aggressive triple negative breast cancer (TNBC). Structure activity relationships study of

derivatives **50** dictate mutant p53 function for apoptotic cell death [63].

*DOI: http://dx.doi.org/10.5772/intechopen.89203*

of anti-diabetic agents development [64].

negative bacterial strains [62].

*Quinazolinone and Quinazoline Derivatives: Synthesis and Biological Application DOI: http://dx.doi.org/10.5772/intechopen.89203*

A series of novel quinazolinone derivatives containing an amino substituted amino moiety were reported for their cytotoxic and antibacterial activities. Among the synthesized compounds **47**–**49** showed broad-spectrum cytotoxic activities giants at least four cancer cell lines at low concentrations. Compounds **44**–**46** exhibited good to moderate antibacterial activities against gram positive and gram negative bacterial strains [62].

Quinazolinone derivatives manipulate mutant p53 proteins and their corresponding cellular response in p53 mutant cancer cells. Compounds **50** and **51** exhibited promising broad-spectrum anti-cancer effects, while **50** demonstrated selective and exclusive inhibition activity in p53 mutant cancer cell lines. Quinazolinone derivatives **50** dictate mutant p53 function for apoptotic cell death [63].

2-(4-bromophenyl)-quinazolin-4(3H)-one (**52A**) and 2-(4-chlorophenyl) quinazolin-4(3H)-one (**52B**) exhibited α-glucosidase inhibitory activity with IC50 values of 12.5 ± 0.1 lM and 15.6 ± 0.2 lM, respectively. Spectroscopy methods were performed to analyze the inhibitory mechanisms of both compounds on α-glucosidase. The outcome of inhibitory mechanism disclosed, that the compounds, inhibited α-glucosidase in reversible and non-competitive manner. Briefly, the quinazolinone derivatives could be potentially promising candidates in the field of anti-diabetic agents development [64].

RAD51 is an essential component of the homologous recombination DNA repair pathway and is over expressed in drug-resistant cancers, including aggressive triple negative breast cancer (TNBC). Structure activity relationships study of

*Quinazolinone and Quinazoline Derivatives*

compare to other synthesized Azaisatins [60].

MCF-7 cell viability [59].

Plausible pathways induced by inhibitors were assessed by evaluating the cytotoxic effect of inhibitors such as 3-(5-chloro-2-hydroxybenzylideneamino)- 2-(5-chloro-2-hydroxyphenyl)-2,3-dihydroquinazolin-41(H)-one (**35**) and 3-(5-nitro-2-hydroxybenzylideneamino)-2-(5-nitro-2-hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (**36**) on MCF-7, MDA-MB-231, MCF-10A and WRL-68 cells. MTT assay results of both the compounds showed significant inhibition of

Azaisatins derivative containing 4(3H) quinazolinones has been designed and synthesized and were screened for their potential antimicrobial activities, which exhibited some authentic results towards testing organism *in vitro* and *in vivo* studies. Azaisatins derivatives with –C6H13 (**40**) display good antimicrobial activity

Quinazolinone derivatives containing 3-acrylamino motifs were screened for antifungal activities against four phytopathogenic fungi by minimum inhibitory concentration (MIC) method. Compounds **41**–**43**, exhibited broad antifungal

activities and substituent's play important role in activities [61].

**82**

quinazolinone derivatives showed that inhibitor (**53**) as a novel RAD51 inhibitor exhibited up to 15-fold enhanced inhibition of cell growth. Furthermore, inhibitors 17 notably hamper TNBC cell sensitivity to DNA damage. This would be potentially targeted therapy for cancer treatment [65].

A series of novel carbazolyloxy phenylquinazoline derivatives have been developed as angiotensin converting enzyme (ACE) inhibitors. Amongst them compounds (**54**–**56**) showed maximum inhibitory potency in enzyme based assays. The most potent (**54**–**56**) compounds have common active site with the Lisinopril binding site [66].

Compounds, 3-(5-chloro-2-hydroxybenzylideneamino)-2-(5-chloro-2 hydroxyphenyl)-2,3-dihydroquinazolin-41(H)-one (**57**) and 3-(5-nitro-2 -hydroxybenzylideneamino)-2-(5-nitro-2-hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (**58**) were screened for their cytotoxic effect on MCF-7, MDA-MB-231, MCF-10A and WRL-68 cells. The mechanism involved in apoptosis, induced by compound **57** and **58** was also evaluated. Additionally, caspase-8 illustrates significant potency, followed by inhibition of NF-κB activation in **57**- and **58**-treated MCF-7 cells. The results indicated that A and B could induce apoptosis via a mechanism that involves either extrinsic or intrinsic pathways [59].

**85**

*Quinazolinone and Quinazoline Derivatives: Synthesis and Biological Application*

as new research into study of medicinal chemistry related field.

The author declares no conflict of interest.

Substituted quinazolinones derivatives were tested for their antimicrobial activity against Gram-negative bacteria and Gram-positive bacteria. Among the prepared products, 3-benzyl-2-(4-chlorophenyl) quinazolin-4(3H)-one (**3a**) was found to exhibits the most potent *in vitro* anti-microbial activity against

Over the past few decades, more effort has been established into searching of better drugs with minimal side effects. Herein number versatile synthetic procedures are discussed for the synthesis of quinazolinone and quinazoline derivatives. In general, quinazolinone and quinazoline derivatives are known to possess wide range of activities. A specific activity depends on the substituent present at an appropriate position of quinazoline. The study of natural and synthetic quinazolinone and quinazoline derivatives identified as potentially promising candidates for developing as novel therapeutic agents. There is possibility for further development

Department of Science and Technology, India (DST-SERB/ECR/2015/000363)

Department of Physical Sciences, Institute of Advanced Research, Gandhinagar,

© 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: satyendramishra1@gmail.com

provided the original work is properly cited.

*DOI: http://dx.doi.org/10.5772/intechopen.89203*

*Staphylococcus aureus*.

**Acknowledgements**

**Conflict of interest**

**Author details**

Satyendra Mishra

Gujarat, India

to SM.

**4. Conclusions**

*Quinazolinone and Quinazoline Derivatives: Synthesis and Biological Application DOI: http://dx.doi.org/10.5772/intechopen.89203*

Substituted quinazolinones derivatives were tested for their antimicrobial activity against Gram-negative bacteria and Gram-positive bacteria. Among the prepared products, 3-benzyl-2-(4-chlorophenyl) quinazolin-4(3H)-one (**3a**) was found to exhibits the most potent *in vitro* anti-microbial activity against *Staphylococcus aureus*.

### **4. Conclusions**

*Quinazolinone and Quinazoline Derivatives*

targeted therapy for cancer treatment [65].

binding site [66].

quinazolinone derivatives showed that inhibitor (**53**) as a novel RAD51 inhibitor exhibited up to 15-fold enhanced inhibition of cell growth. Furthermore, inhibitors 17 notably hamper TNBC cell sensitivity to DNA damage. This would be potentially

A series of novel carbazolyloxy phenylquinazoline derivatives have been developed as angiotensin converting enzyme (ACE) inhibitors. Amongst them compounds (**54**–**56**) showed maximum inhibitory potency in enzyme based assays. The most potent (**54**–**56**) compounds have common active site with the Lisinopril

Compounds, 3-(5-chloro-2-hydroxybenzylideneamino)-2-(5-chloro-2 hydroxyphenyl)-2,3-dihydroquinazolin-41(H)-one (**57**) and 3-(5-nitro-2

nism that involves either extrinsic or intrinsic pathways [59].


**84**

Over the past few decades, more effort has been established into searching of better drugs with minimal side effects. Herein number versatile synthetic procedures are discussed for the synthesis of quinazolinone and quinazoline derivatives. In general, quinazolinone and quinazoline derivatives are known to possess wide range of activities. A specific activity depends on the substituent present at an appropriate position of quinazoline. The study of natural and synthetic quinazolinone and quinazoline derivatives identified as potentially promising candidates for developing as novel therapeutic agents. There is possibility for further development as new research into study of medicinal chemistry related field.

#### **Acknowledgements**

Department of Science and Technology, India (DST-SERB/ECR/2015/000363) to SM.

#### **Conflict of interest**

The author declares no conflict of interest.

#### **Author details**

Satyendra Mishra Department of Physical Sciences, Institute of Advanced Research, Gandhinagar, Gujarat, India

\*Address all correspondence to: satyendramishra1@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.
