Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 15  |  Issue : 3  |  Page : 98-131

Synthetic approaches and potential bioactivity of different functionalized quinazoline and quinazolinone scaffolds


1 Department of Therapeutical Chemistry, National Research Centre, Pharmaceutical and Drug Industries Research Division, Dokki, Egypt
2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt
3 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia

Date of Submission15-Mar-2016
Date of Acceptance30-May-2016
Date of Web Publication5-Jan-2017

Correspondence Address:
Manal M Anwar
Department of Therapeutical Chemistry, National Research Centre, Pharmaceutical and Drug Industries Research Division, El-Bohowth Street, PO Box 12622, Dokki, 0123456, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-4315.197580

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  Abstract 

Drug discovery and optimization constitutes one of the most important targets in medicinal chemistry. Because of their wide bioactivity spectra, nitrogen-containing heterocycles have received significant attention in many bio(organic) studies. The current review is a simple summary of different environmentally benign synthetic procedures that afford a variety of quinazoline and quinazolinone scaffolds with promising biological potential. The molecular modeling of various classes has also been discussed to elucidate the molecular reasons that led to the observed inhibition profile of different protein kinases, including which amino acids in their active sites would be involved in the anticipated bonding interactions. Furthermore, this article aims to investigate which classes deserve further development to get more specific and more potent quinazoline and quinazolinone candidates in various biological targets.

Keywords: biological activities, molecular docking, protein kinase inhibitors, quinazoline, quinazolinone, synthesis


How to cite this article:
Kamel MM, Zaghary WA, Al-Wabli RI, Anwar MM. Synthetic approaches and potential bioactivity of different functionalized quinazoline and quinazolinone scaffolds. Egypt Pharmaceut J 2016;15:98-131

How to cite this URL:
Kamel MM, Zaghary WA, Al-Wabli RI, Anwar MM. Synthetic approaches and potential bioactivity of different functionalized quinazoline and quinazolinone scaffolds. Egypt Pharmaceut J [serial online] 2016 [cited 2017 Oct 18];15:98-131. Available from: http://www.epj.eg.net/text.asp?2016/15/3/98/197580


  Introduction Top


Quinazoline 1 is 1,3-diazanaphthalene. This nucleus is also called 5,6-benzopyrimidine or benzo[a]pyrimidine or phenmiazine [1]. Its 4-oxo derivative is named 4(3H)-quinazolinone 2 ([Figure 1]) [2]. Depending on the wide spectra of their different pharmacological activities, both nuclei have attracted considerable attention from many scientists and chemists worldwide. They exhibit antimalarial [3], antimicrobial [4], anti-inflammatory [5], anticonvulsant [6], antihypertensive [7], antidiabetic [8], and antitumor activities [9],[10],[11]. At the same time, various quinazoline derivatives are considered, such as inhibitors of various forms of cellular phosphorylation [12], in addition to their essential activities in the central nervous system (CNS), such as ligands for benzodiazepine and γ-aminobutyric acid receptors [13]. Also, many quinazoline derivatives act as DNA-binding agents or as effective adrenergic blockers [14].
Figure 1: Chemical structures of quinazoline 1 and 4(3H)-quinazolinone 2.

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Many quinazolinone derivatives also constitute the building blocks for about 150 natural alkaloids isolated from various classes of the plant kingdom, from microorganisms, and from animals ([Figure 2]). Earlier studies conducted in the 1950 s and 1960 s led to the discovery of febrifugine, a quinazolinone alkaloid, which possesses antimalarial potential, from the Chinese plant aseru (Dichroa febrifuga Lour) [15].
Figure 2: Structures of alkaloids incorporating quinazolinone frameworks.

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  Chemistry of quinazolines Top


Gabriel [16] was the first scientist to prepare quinazoline nucleus in the laboratory in 1903. Widdege [17] was the first scientist to propose the name quinazoline (German: chinazolin) for this nucleus on the basis of its appearance as an isomer with the quinoxaline ring [18].

The synthesis of various compounds containing quinazoline as the main nucleus is largely based on the substitution patterns on the 1,3-diazine moiety of the system.

4(3H)-Quinazolinones

The facile preparation of quinazolin-4(3H)-one (4), which involves heating the logical starting material anthranilic acid (3) with excess formamide in an open container at 120°C, was known as Niementowski reaction ([Figure 3]) [19]. In addition, Ahmed et al.[20] used formyl anthranilamide (5) for the preparation of 4 by means of intramolecular condensation reaction ([Figure 3]).
Figure 3: Preparation of 4(3H)-quinazolinone using anthranilic acid or formyl anthranilamide.

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The 7-chloro-substituted derivative (7) [21] has been prepared through condensation of 4-chloroanthranilic acid amide (6) with triethyl orthoformate ([Figure 4]).
Figure 4: Preparation of 7-chloroquinazolin-4(3H)-one.

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2-Substituted-4(3H)-quinazolinones and quinazolines

The general method for producing the cinnamamide derivative 10 involves the treatment of 2-aminobenzonitrile (8) with 3-phenyl cinnamoyl chloride (9). Under alkaline conditions, intramolecular cyclization was carried out to afford 2-styryl-4(3H)-quinazolinone (11) [22] ([Figure 5]). This procedure was tolerated to a wide range of different substituted benzene rings, and in most cases the intermediate N-(2-cyanophenyl)cinnamamide (10) could be isolated.
Figure 5: Preparation of 2-styryl-4(3H)-quinazolinone derivatives.

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Refluxing of anthranilamide (12) with aryl, alkyl, or heteroaryl aldehydes or ketones (13) in 2, 2, 2-trifluoroethanol in the absence of catalysts led to the formation of 2-substituted-2,3-dihydro-4(1H)-quinazolinones (14) in excellent yields. The characteristic physiochemical properties of fluorous solvents, such as low nucleophilicity, high polarity, and high ability of hydrogen bond donation, has led to their utilization in organic reactions ([Figure 6]) [22].
Figure 6: Preparation of 2-substituted-2,3-dihydro-4(1H)-quinazolinones. TFE, 2,2,2-trifluoroethanol.

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Microwave (MW) conditions were used by Rad-Moghadam and Mohseni [23] to synthesize 2-substituted-4(3H)-quinazolinones (16). This strategy involved the reaction of anthranilic acid (3), ammonium acetate, and orthoesters (15) to yield the desired products ([Figure 7]).
Figure 7: Preparation of 2-substituted-4(3H)-quinazolinone derivatives.

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Complete conversion of anthranilic acid (3) to 2-substituted-4(3H)-quinazolinones was gained in efficient yields (75–84%) under MW conditions over 10 min at a temperature of 200°C at 200 W. Heating anthranilic acid (3), acetic anhydride, and formamide in a sealed tube at 200°C (200 W) for 10 min leads to rapid decomposition of formamide during the interaction of anthranilic acid and anhydride. The formed ammonia (in situ) reacts with the benzoxazine derivative (17). An efficient yield of 3-methylquinazolin-4-one (18) was achieved after purification ([Figure 8]) [24].
Figure 8: Preparation of 3-methylquinazolin-4-one under microwave (MW) conditions.

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Abdel-Jalil et al. [25] revealed that the intermediate Schiff's bases (19) were synthesized in good yields within 3 h at 70 °C through treatment of anthranilamide (12) with suitable aldehydes in ethyl alcohol. The conversion of Schiff's bases to the corresponding 2-substituted quinazolinones (16) was carried out within 2 h in refluxing ethanol containing three equivalents of copper chloride. However, these quinazolinones (16) could be also obtained in 88% yield through a one-step reaction procedure by refluxing ethanolic solution of anthranilamide (12), the appropriate aldehyde, and copper chloride for 2–3 h ([Figure 9]).
Figure 9: Preparation of 2-substituted quinazolinones.

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Erba et al. [26] introduced a three-component reaction to obtain 2-alkylquinazolines (22). First, a suitable aldehyde was allowed to react with morpholine to form the intermediate (20). In the second step, compound 20 was treated with an aryl azide to obtain the 1, 2, 3-triazoline derivatives (21) in good yields. Further, the triazolines (21) were exposed to an ethanolic solution saturated with ammonia in a sealed vessel at 150°C to afford the desired quinazoline products (22). Alternatively, the same compounds (22) could be obtained when the triazolines (21) were treated with ammonium acetate in boiling toluene within half an hour. The intramolecular cyclization of the triazolines afforded the 2-alkylquinazoline derivatives (22) in 92–95% yields ([Figure 10]).
Figure 10: Preparation of 2-alkylquinazoline derivatives.

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Kotsuki et al. [27] developed condensation of cyano-activated and nitro-activated o-fluoro-benzaldehydes (23) with amidine (24) to afford different substituted quinazoline derivatives (25) in promising yields. Cyclization of the imine with the aldehydic functional group occurred. Nucleophilic substitution of the fluorine atom was carried out leading to intramolecular cyclization to afford the quinazoline derivatives (25). The reaction was performed under reflux in acetonitrile containing potassium carbonate in the presence of powdered molecular sieves. Chromatographic purification was carried out for the crude products ([Figure 11]).
Figure 11: Preparation of different substituted quinazoline derivatives.

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The amino-quinazolin-4(3H)-one (28) was derived by Hess et al. [28]. It was synthesized by means of the reaction of the corresponding methyl anthranilate (26) with an excess amount of guanidine (27) in ethyl alcohol containing sodium ethoxide. The yield of this reaction was moderate ([Figure 12]).
Figure 12: Preparation of 2-amino-quinazolin-4(3H)-one.

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3-Substituted-4-quinazolinones

Clark and Wagner [29] have reported the use of isatoic acid anhydride (29) for the preparation of 3-substituted-4(3H)-quinazolinone derivatives (30) by heating with primary amines and triethyl orthoformate ([Figure 13]).
Figure 13: Preparation of 3-substituted-4(3H)quinazolinone derivatives.

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Majo and Perumal [30] developed the 3-substituted-4(3H)quinazolinones (34 and 35) in which the Vilsmeier reagent (chloromethyleneiminium salt) (32) reacted with 5-substituted-2-amino benzoic acid derivatives (31) to give the corresponding acid chlorides (33), which reacted through two possible routes: A and B ([Figure 14]).
Figure 14: Preparation of 3-substituted-4(3H)quinazolinone derivatives.

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4-Substituted-quinazolines

Because of the reported high biological potential of 4-arylaminoquinazolines as anticancer agents, there has been renewed interest in their syntheses [31]. Amidines (36) were readily formed by the interaction of 2-aminobenzonitrile (8) with different substituted anilines and anhydrous aluminum chloride. It was observed that the highest yield of the amidine intermediates 36 was achieved by the use of excess amounts of suitable aniline and aluminum chloride. Limited production of the intermediates (36) was obtained from the pattern of aromatic substitution on the aniline ring. 2-Aminobenzonitrile (8) did not react with 3,4-dichloroaniline or nitroanilines possibly because the nucleophilicity of the amino functionality is minimized in each case. Good yields (70–92%) of the 4-arylaminoquinazoline derivatives (37) were achieved when the 2-amino-N-arylbenzamides (36) were heated with 85% formic acid ([Figure 15]) [32].
Figure 15: Preparation of 4-arylaminoquinazoline derivatives.

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An efficacious method for the preparation of 4-anilinoquinazolines (40) was reported by Tsou et al. [33]. Condensation of 5-nitroanthranilonitrile (38) with dimethylformamide-dimethyl acetal yielded compound 39. When compound 39 was heated with 3-bromoaniline in acetic acid it afforded the target quinazoline derivative (40) in an outstanding yield. This method is beneficial as the synthesis of the quinazoline ring system and its conjugation with the 4-anilino moiety take place in the same step ([Figure 16]).
Figure 16: Preparation of 4-anilinoquinazoline derivatives.

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The treatment of (E)-N′-(2-cyano-3-fluorophenyl)-N,N-dimethylformimidamide (41) with 2-chlorobenzylamine (42) to obtain the quinazoline compound 43 using MW irradiation was reported by Yoon et al. [34] ([Figure 17]).
Figure 17: Preparation of N-(2-chlorobenzyl)-1-(5-fluoroquinazolin-4-yl)methanamine derivatives. MW, microwave.

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2,3-Disubstituted-4(3H)-quinazolines

Ager et al. [35] obtained 2,3-disubstituted-4(3H)-quinazolinone derivatives (45) through the treatment of N-acylanthranilic acid (44) with the appropriate aryl amines in the presence of phosphorous oxychloride ([Figure 18]).
Figure 18: Preparation of 2,3-disubstituted-4(3H)-quinazolinone derivatives.

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Furthermore, a group of researchers [36] reported that the 3-substituted-2-metyl quinazolinones (47) were prepared by the reaction of methyl-2-acetamido benzoate (46) with the desired amine in the presence of trimethyl aluminum in 1,2-dichloroethane ([Figure 19]).
Figure 19: Preparation of 3-substituted-2-metyl quinazolinones.

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Benzoxazinone derivatives are the most common intermediates in the formation of 2,3-disubstituted quinazolinone derivatives. Welch et al. [37] stated that refluxing of anthranilic acid (3) with acetic anhydride in acetic acid yielded 2-methyl-4H-benzo[d] [1,3]oxazin-4-one (17), which was heated with amines in acetic acid or ethanol to yield the corresponding quinazolinones (48) ([Figure 20]).
Figure 20: Preparation of 2,3-disubstituted quinazolinone derivatives.

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Dandia et al.[38] disclosed that the 4-benzoxazinone derivative (50) was synthesized in situ by the cyclodehydration of 2-phenylacetylamino benzoic acid (49) with acetic anhydride using inorganic solid supports. Also, the condensation of the 4-benzoxazinone derivative (50) with various para/meta/ortho-substituted anilines has been studied to obtain the desired derivatives (51 and 52) ([Figure 21]).
Figure 21: Preparation of 3-substituted-2-benzylquinazolin-4(3H)-one derivatives.

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Moreover, a rapid one-step MW reaction by cyclocondensation of anthranilic acid (3), phenyl acetyl chloride (53), and different substituted aniline derivatives for the synthesis of quinazoline derivatives 54 was documented by Dandia et al.[38]. The reaction yield was 87–92% ([Figure 22]) [38].
Figure 22: Preparation of 3-substituted-2-benzylquinazolin-4(3H)-one derivatives.

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Lee et al. [39] developed a facile method for the formation of 3-substituted-2-cyano-4(3H)-quinazolinone compounds (57) in moderate to good yields by the treatment of primary alkylamines with the intermediate derivative (56). The latter compound was synthesized by the treatment of methyl anthranilate (26) with 4,5-dichloro-1, 2, 3-dithiazolium chloride (Appel's salt) (55) in pyridine. Its yield was 50%. The cyano group of quinazolinone products (57) could be replaced by different nucleophiles to furnish the corresponding 2-substituted quinazolinone derivatives in high yields. This leads to the synthesis of new quinazoline systems rapidly and efficiently ([Figure 23]).
Figure 23: Preparation of 3-substituted-2-cyano-4(3H)-quinazolinone derivatives. THF, tetrahydrofuran.

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2,4-Disubstituted-4(3H)-quinazolinones and quinazoline

The synthesis of 4-aminoquinazolines (58) using MW irradiation was documented by Seijas et al. [40]. This reaction was performed by the treatment of the cyanoaromatic derivatives with anthranilonitrile (8) in a MW oven. 2-(Thiophen-2-yl)quinazolin-4-amine was gained at a high yield by heating anthranilonitrile, 2-thienylnitrile, and potassium tert-butoxide in a test tube for 60 s. A remarkable decrease in reaction time, the absence of solvents, and the use of a base in a catalytic amount are attractive features of this method ([Figure 24]).
Figure 24: Preparation of 4-aminoquinazoline derivatives. MW, microwave; t-BUOK, potassium tert-butoxide.

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Mizuno et al. [41] reported the preparation of 2,4-dihydroxyquinazoline derivatives using various 2-aminobenzonitrile compounds 8 and carbon dioxide containing 1,8-diazabicyclo [5, 4, 0]undec-7-ene under mild conditions. The reaction was carried out using a suitable base to synthesize the carbamate salt (59). In the subsequent step the oxygen of carbamate moiety attacked the nitrile group, leading to nucleophilic cyclization. Then, rearrangement took place to produce the intermediate (60), which was protonated to give the target 2,4-dihydroxyquinazolines (61) ([Figure 25]).
Figure 25: Preparation of 2,4-dihydroxyquinazoline derivatives. DBU, 1,8-diazabicyclo[5,4,0]undec-7-ene.

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The thermolysis of 5-methoxy-(3H)-1,4-benzodiazepines to furnish 4-methoxyquinazoline derivatives was studied by Kaname et al. [42]. Ring contraction was the proposed mechanism. The 4-methoxyquinazoline derivatives (63) were the only obtained products in moderate yields (41–46%) upon heating the 5-methoxy-(3H)-1,4-benzodiazepines (62) in refluxing diphenyl ether at 160–170°C for 6 h ([Figure 26]).
Figure 26: Preparation of 4-methoxyquinazoline derivatives.

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Zielinski et al. [43] developed a procedure to synthesize dimethylquinazoline-2,4-diamine derivatives by treating chloroamidines with dialkylcyanamides. Reaction of various phenyl isocyanate derivatives (64) with N,N-diethylamine led to the formation of the substituted urea derivatives (65), which were subsequently chlorinated with phosphorus pentachloride to produce the corresponding compounds (66). As an example, 2-(N,N-diethylamino)-4-(N,N-dimethylamino)quinazoline (68) was synthesized in 79% yield by cyclization of compound 67, which was obtained by the treatment of chloroamidine (66) with N,N-dimethylcyanamide ([Figure 27]).
Figure 27: Preparation of dimethylquinazoline-2,4-diamine derivatives.

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The reaction of various Grignard reagents with 2-aminobenzonitrile (8) resulting in the formation of intermediates (69) was demonstrated by Bergman et al.[44]. The formed derivatives (69) were very important for obtaining 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 ([Figure 28]).
Figure 28: Preparation of various 2,4-disubstituted quinazoline derivatives.

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  Pharmacological applications Top


Anticancer activity

Aurora proteins inhibitors

Aurora proteins constitute a small class of serine/threonine kinases that are generated during the period of mitosis. They play important functions in chromosomal segregation and cytokinesis. There are three types of aurora kinases formed in human beings: aurora A, B, and C. These protein kinases have been recently considered attractive drug targets because of their importance in mitosis and their irregular overexpression in cancer cells [45]. Inhibition of both aurora A and aurora B causes the formation of different cellular phenotypes. Synthesis of a set of 5-acetanilide-3-aminopyrazole(3-pyrazole)-substituted quinazoline derivatives that showed high selectivity for aurora B over aurora A resulted in the synthesis of AZD1152 ([Figure 29]). AZD1152 has exhibited significant anticancer activity in different preclinical models and was recently used in phase I clinical experiments [46]. Taking into consideration the structural characteristics of AZD1152, a novel class of 1-acetanilide-4-aminopyrazole-substituted quinazoline compounds (compounds 70) was formed by Foote et al. [46].
Figure 29: Structures of quinazoline derivatives as aurora protein inhibitors.

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In summary, it has been observed that the 4-pyrazole derivatives exhibited significant inhibition against aurora B kinase, whereas less activity was observed against aurora A. Potent cellular activities were achieved by the presence of fluoro groups favorably at C2 and C3 of the phenyl ring. The conjugation of different basic side chains with the quinazoline ring system at C7 also delivered high activity. The displacement of the methoxy group with a proton at quinazoline-C6 enhanced the selectivity for aurora B over aurora A. The cellular potency for the 4-pyrazole derivatives is significant and even higher than that of the corresponding 3-pyrazole analogs. Many 4-pyrazole derivatives exhibited cellular EC50 less than 10 nmol/l and some, such as compounds 70, showed cellular EC50 less than 1 nmol/l ([Figure 29]). The optimized compound 71 exhibited potency at doses less than that in other reported series in preclinical in-vivo models ([Figure 29]).

Topoisomerase (I and II) inhibitors

Benzimidazole–quinazoline hybrids, substituted with various secondary amines, demonstrate the effects of electron-donating and electron-accepting nitrogen groups within the groups [47],[48]. Lipophilicity of polar compounds, an important property for the activity of different drugs, increases because of the attachment of alkyl or allyl functionalities to the benzimidazole ring and aryl moieties to the quinazoline ring ([Figure 30]).
Figure 30: Proposed hypothetic model for hybrid compounds.

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Novel regioisomeric hybrids (3-allyl-2-methyl-3H-benzimidazol-5-yl)–(2-substituted-quinazolin-4-yl)-amine derivatives (7275) and (1-allyl-2-methyl-1H-benzimidazol-5-yl)–(2-substituted-quinazolin-4-yl)-amine derivatives (7677) were derived by Sharma et al.[47] and evaluated as novel compounds for their anticancer activity. Preliminary in-vitro antitumor screening proved that the derivatives 72 and 73 had potent inhibitory effect (>60%) for the growth of most of the tested tumor cell lines, whereas all the compounds exhibited selective activity toward the renal cancer cell line A498. Also, the anticancer evaluation confirmed that (3-allyl-2-methyl-3H-benzimidazol-5-yl)–(2-amino-quinazolin-4-yl)-amine derivatives (72, 73, and 75) are more effective anticancer compounds than their regioisomeric analogs (1-allyl-2-methyl-1H-benzimidazol-5-yl)–(2-aminoquinazolin-4-yl)-amine derivatives 76 and 77 ([Figure 31]). Molecular docking studies of compound 73 indicated that the formation of hydrogen bonds with the active sites of ribonucleotide reductase, topoisomerase I, and topoisomerase II also enhanced its potency. These benzimidazole and quinazoline hybrids could be further used as anticancer compounds of significant potency. Further derivatization and optimization studies of the anticancer profiles of these compounds are currently ongoing.
Figure 31: Structures of hybrids of benzimidazole and quinazoline analogs.

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Dual Src/Abelson murine leukemia viral oncogene homolog 1 (Abl) kinase inhibitors

The design and preparation of various new 4-benzothiazole amino quinazoline analogs were carried out by Cai et al. [49] ([Figure 32]). The synthesis of these novel hybrids depends on the structure–activity relationship (SAR) analysis of dasatinib, which was used as the leading compound, and also on the basic drug design principles of ring addition and combination.
Figure 32: Novel 4-benzothiazole amino quinazoline derivatives.

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In-vitro cytotoxic activity evaluation by MTT-based assay was carried out for all target compounds. The activity was investigated against six human cancer cell lines (HCT-116, DLD1, K562, U937, A549, and NCI-H661). The obtained data showed that most of the tested derivatives exhibited a remarkable growth inhibition against the six cell lines compared with the parental dasatinib. In addition, the target compounds were tested as Src and Abl kinase inhibitors. The enzyme inhibitory assay showed that the derivatives bearing 2-methyl piperidine moiety attached to the quinazoline ring are the most potential dual Src/Abl kinase inhibitors. Thus they are potential lead ligands to be prepared and optimized as alternatives for the current dasatinib therapy or for patients who show imatinib resistance, potentially by simultaneously blocking multiple receptor tyrosine kinase (RTK) signaling pathways ([Figure 32]).

Epidermal growth factor receptor and vascular endothelial growth factor receptor 2 inhibitors

Novel 2-chloro-4-anilino-quinazolines were designed and examined as inhibiting agents for both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR-2) protein kinases [50]. It has been documented that EGFR and VEGFR-2 are validated targets in cancer therapy, and combined inhibition might be synergistic for both antitumor activity and resistance prevention. The results of the enzyme inhibitory test proved that 2-chloro-4-anilino-quinazoline derivatives produced potential activity against both EGFR and VEGFR-2. Compound 79e was nearly seven times more active against VEGFR-2 and nearly 11 times more active against EGFR in comparison with the prototype 78 that was previously synthesized by Abouzid and Shouman [51]. SAR and molecular docking studies investigated the pharmacophoric moieties for both EGFR and VEGFR-2 protein kinases and investigated the worth of the presence of a hydrogen bond donor at the aniline-C4 for binding with the conserved glutamate and aspartate amino acids in the binding sites of both EGFR and VEGFR-2, which promotes a significant increase in potency ([Figure 33]).
Figure 33: Structures of novel 2-chloro-4-anilino-quinazolines.

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Also, new 6,7-disubstituted-4-(arylamino)quinazoline derivatives were synthesized by Zhang et al. [52]. These compounds were developed to function as irreversible inhibiting agents for the EGFR protein kinase. Fortunately, they revealed significant activity. Compared with afatinib, some of them revealed significant enhanced potency against H1975 cells (EGFR-T790 M). Moreover, the optimized compounds 80 and 81 also showed acceptable pharmacokinetic properties and oral bioavailability. Depending on the developed safety and activity against EGFR-T790 M resistance, the derivatives 80 and 81 could be used for further development and optimization in future research ([Figure 34]).
Figure 34: Structures of 6,7-disubstituted-4-(arylamino) quinazoline derivatives.

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Erythropoietin-producing hepatocellular receptor tyrosine kinase A inhibitors

The erythropoietin-producing hepatocellular (Eph) RTKs play very important roles in various physiological and pathological conditions, including embryogenesis, patterning, neuronal targeting, vascular development, and cancer progression. There is overexpression of Eph RTKs and their cell-presented ligands, ephrins, in a large number of cancer types such as breast, lung, gastrointestinal cancers, and neuroblastomas. At present, there are two main classes of Eph RTKs: EphA (EphA1–10) and EphB (EphB1–6) [53]. EphA2 has particularly been correlated to breast, prostate, lung, ovarian, and cervical cancer as well as to malignant melanoma. Further, the degree of malignancy and poor prognosis depend on the level of EphA2 expression in the tumor cells. Novel 4-substituted quinazoline derivatives bearing the 7-(morpholin-2-ylmethoxy) group (compounds 82) were designed and prepared by Lim et al. [53]. The new derivatives showed significant inhibition toward EphA2. The most potent compound was 82e ([Figure 35]).
Figure 35: Structures of 4-substituted quinazoline derivatives bearing 7-(morpholin-2-ylmethoxy) group.

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Poly(ADP-ribose)polymerase-1 enzyme inhibitors

It was demonstrated that poly(ADP-ribose)polymerase-1 (PARP-1) plays a pivotal role in the repair of single-strand breaks of DNA through the base excision repair pathway. Therefore, the inhibition of PARP-1 enzyme can synergize the cytotoxic effects of the DNA-damaging agents [e.g. temozolomide (TMZ), cyclophosphamide, and camptothecin], which cause lesions normally repaired by the base excision repair pathway [54]. Novel 1-benzyl-quinazoline-2,4(1H,3H)-dione derivatives were designed and prepared as human PARP-1-inhibiting agents. Depending on the SAR studies, it was found that the quinazoline-2,4(1H,3H)-diones (83) produce potent inhibitory activity against the PARP-1 enzyme of IC50 values at nanomolar levels. Compound 83c produced a potent dual-inhibition effect against PARP-1 and PARP-2 and it could selectively damage the breast cancer cells MX-1 and MDA-MB-468 with mutated BRCA1/2 and PTEN, respectively, compared with homologous recombination proficient cell types such as the breast cancer cell line MDA-MB. Moreover, compound 83c exhibited the strongest potentiation effect of potentiation factor (PF50) on TMZ in MX-1 cells (PF50 = 3.77) ([Figure 36]).
Figure 36: Structures of 1-benzyl-quinazoline-2,4(1H,3H)-dione derivatives.

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DNA-damaging activity

Nitrogen mustards are the earliest bifunctional alkylating agents. They interrupt DNA biosynthesis, leading to DNA disruption and damage. The biggest disadvantage of these drugs is their high genotoxicity, which produces many side effects on the patients [55]. Many nitrogen mustards have been synthesized in clinical applications. Chlorambucil, melphalan, and cyclophosphamide are the most important drugs belonging to this class. Hoping to obtain novel potential antiproliferative derivatives, a new class of quinazoline-nitrogen mustards (compounds 84, 85, and 86) were designed and synthesized by Li et al. [55]. In this work, a nitrogen mustard group was directly introduced to the quinazoline ring depending on its efficiency as an ideal carrier for nitrogen mustards.

Most of the new quinazoline-nitrogen mustard derivatives revealed selective cytotoxicity toward specific types of cancer cells, and the conjugation of the quinazoline ring generally reduced the virulent side effects of the nitrogen mustard. Various studies have demonstrated that compound 85b shows cell cycle delay and arrests the cell cycle progression predominantly at the S and G2/M boundary, and produces cell apoptosis, while its host toxicity is small. Thus, this work revealed some methods for synthesis and optimization of new quinazoline-nitrogen mustards of high tumor affinity taking quinazoline ring as a nitrogen mustard transporter ([Figure 37]).
Figure 37: Structures of quinazoline-nitrogen mustard derivatives.

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Antimitotics and tubulin polymerization inhibiting activity

A novel class of pyrrolo [3,4-h]quinazolines has been successfully prepared by fusion of the pyrimidine ring with the isoindole moiety ([Figure 38]) [56]. Some of the new compounds have shown interesting cytotoxicity in many tumor cell lines and were active even in a multidrug-resistant cell line. The most cytotoxic derivatives, 87a–d and 88e, induced cell death mainly by apoptosis, as demonstrated by the onset of the apoptotic peak in cell cycle analysis and by the classical annexin-V/PI test. Moreover, the involvement of mitochondria and, in a later stage, of lysosomes was demonstrated. It was observed that most cytotoxic quinazoline derivatives act as antimitotics and inhibit tubulin polymerization in vitro. These derivatives also presented some antiangiogenic effects that could be useful for disrupting the tumor vascular network, thus inducing extensive cell death at its core.
Figure 38: Structures of pyrrolo[3,4-h]quinazoline derivatives.

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A new set of 6-chloro-2-p-tolylquinazolinone compounds (89 and 90) and 9-chloro-5-p-tolyltetrazolo [1,5-c]quinazoline (91) was prepared in order to examine them as in-vitro anticancer agents ([Figure 39]) [57]. The tested candidates were examined against 60 cancer cell lines at 10 μmol/l concentration. The obtained data showed that compounds 89 and 90 had significant wide-spectrum antitumor potency. The derivative 91 selectively inhibited the growth of non-small-cell lung cancer using 5-fluorouracil as a reference drug. Also, it was demonstrated that compound 90 had ∼1.5 fold more potency (mean GI50 = 15.8 μmol/l) in comparison with 5-fluorouracil (mean GI50 = 22.6 μmol/l).
Figure 39: Structures of 6-chloro-2-p-tolylquinazolinone (89, 90) and 9-chloro-5-p-tolyltetrazolo[1,5-c]quinazoline (91) derivatives.

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Mitochondrial translocator protein inhibiting activity

Glioblastoma multiforme (GBM) is the most common and malignant primary human brain tumor with very poor prognosis. Patients diagnosed with GBM usually undergo surgical intervention by Food and Drug Administration for the treatment of late-stage metastatic medullary thyroid cancer, as well as resection, radiation, and chemotherapy using the DNA alkylating agent TMZ, but the mean life expectancy is less than 14 resistance induction because of the activation of DNA repair proteins rendering the drug ineffective [58]. Recent reports indicated that the mitochondrial translocator protein is selectively overexpressed in the brains of GBM patients. In this regard, compounds inducing the mitochondrial permeability transition pore (mPTP) opening through translocator protein targeting were suggested as chemotherapeutic agents for glioma and glioblastoma cells. Elkamhawy et al. [58] reported on novel quinazoline-urea compounds ([Figure 40]). In this study, the mPTP opening was aimed to be inhibited. Most of the bulky derivatives of R2 of the urea side chain exhibited an opposite effect on the mitochondrial membrane potential, which could be a promising approach for GBM therapy. The eight compounds 92 showed excellent selectivity indices for GBM cells compared with a normal astrocyte cell line. Compound 92e manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations accompanied by a safe toxicity profile. Taken as a whole, this report presents compound 92e as a potent, selective, and safe GBM cytotoxic agent, giving new promise for action against TMZ-resistant GBM.
Figure 40: Structures of quinazoline-urea derivatives.

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Transcription factor protein complex (nuclear factor κB) inhibiting activity

Nuclear factor κB (NF-κB) is a transcription factor protein complex. It is present in almost all animal cell types and plays a pivotal role in some tumors and inflammatory responses. It increases the rate of proliferation and inhibits apoptosis, in addition to creating more blood flow to ensure the survival of cancer. Thus, blocking the NF-κB pathway is one of the most important approaches in the cancer therapeutic field. A new class of quinazoline scaffold pharmacophores (93 and 94) of expected high binding affinity with the p50 subunit of NF-κB was designed and synthesized ([Figure 41]) [59]. Biological studies showed that the compounds carrying phenyl substituents at the quinazoline-C2 position appeared to be potent inhibitors of NF-κB function. These candidates also reduced the proliferation rate of many cancer cell lines. The compound 93c exhibited a mean GI50 of 2.88 μmol/l against the NCI-60 cell lines and produced a remarkable apoptosis in the EKVX cell line at a dose of 1 μmol/l.
Figure 41: Structures of 2-sustituted quinazoline derivatives.

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Inducing apoptosis activity

Novel compounds of m-(4-morpholinoquinazolin-2-yl)benzamides were designed, prepared, and characterized by Wang et al. [60] ([Figure 42]). The new derivatives were examined as anticancer agents against two types of human cancer cells (HCT-116 and MCF-7). Most of the candidates exhibited potent antiproliferative activity, especially compound 96, which represented a significant in-vitro potency in the Hoechst staining assay. Furthermore, the cell cycle and apoptosis assay showed that the analog 96 might arrest HCT-116 cells in G2/M and G0/G1 phase and lead to apoptosis. Also, compounds 95 and 96 exhibited selective inhibition of the PI3Kα enzyme, as revealed by the enzyme assay results. Also, western bolt assay proved that analog 96 could block the PI3K/Akt/mTOR pathway. These results directly revealed m-(4-morpholinoquinazolin-2-yl)benzamide derivatives as new antitumor candidates. The SAR of the title compounds reveals that the benzamide moiety is important for the maintenance of the antiproliferative activity of the title compounds. In addition, a trifluoromethoxy moiety at m-position of the amide group and methoxy at six and seven positions of the quinazoline ring are also favorable substituents.
Figure 42: Structures of m-(4-morpholinoquinazolin-2-yl)benzamide derivatives.

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Molecular hybridization led to the design and synthesis of new isatin–quinazoline hybrids ([Figure 43]) [61]. The new hybrids were examined as in-vitro anticancer agents against the liver HepG2, breast MCF-7, and colon HT-29 cancer cell lines. Significant selective inhibition was gained against the HepG2 cancer cell line. The derivatives 97a, 97b, and 97c produced the strongest activity (IC50 = 1.0–2.4 μmol/l). Further, they led to apoptosis in HepG2 cells, as seen by increased proapoptotic protein Bax expression and decreased expression of the antiapoptotic protein Bcl-2, as well as enhanced caspase-3 levels.
Figure 43: Structures of isatin–quinazoline hybrid derivatives.

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Marketed anticancer drugs carrying quinazoline core

The drugs gefitinib (Iressa), erlotinib (Tarceva), and lapatinib (Tykerb) ([Figure 44]), which selectively inhibit the EGFR protein kinase, were approved by the Food and Drug Administration in 2003, 2004, and 2007, respectively. They are active in locally advanced or metastatic cancer chemotherapy [49],[62],[63],[64]. Vandetanib, targeting EGFR and VEGFR-2, was approved in April 2011.
Figure 44: Chemical structures of different anticancer drugs carrying quinazoline pharmacophores.

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Anti-inflammatory activity

New basic 5,6-dihydrobenzo[h]quinazoline derivatives 98a–h carrying various amino groups at positions 2 and 4 were designed and synthesized in order to obtain novel antiplatelet/analgesic and anti-inflammatory agents with a safe gastrointestinal profile ([Figure 45]) [65].
Figure 45: Structures of 5,6-dihydrobenzo[h]quinazolines.

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The new derivatives (98a–h) exhibited variable antiplatelet activity on the in-vitro platelet aggregation test. The derivatives 98a and 98e emerged as having the strongest activity by inhibition of all the aggregating stimuli. The in-vivo examination found that the conjugation of different amino groups at position 4 was important for producing the analgesic potency of compounds 98a–h – in particular, compound 98 h. This derivative exhibited 51% pain inhibition at a dose that did not lead to any sedation as the treated mice exhibited the same degree of locomotor activity as those treated with the vehicle only, in the same experiment. Data showed that 98a and 98 h inhibited both cyclooxygenase (COX) 1 (maximal inhibition = 50.5 and 28.7%, respectively) and COX2 (maximal inhibition = 38.6 and 50.7%, respectively) at a dose of 1 mmol/l. These data confirm the hypothesis that both 98a and 98 h have promising antiplatelet activity with no relation to COX inhibition, acting through other modes of action. Computational study on compounds 98a and 98 h was also performed. Docking simulation studies of both compounds showed that compound 98a directed the dihydrobenzo[h]quinazoline portion toward Tyr355, Leu523, and Leu531 and can form one H-bond with the key residue Tyr385 through the aniline moiety nitrogen atom, whereas the anilino group of compound 98 h is directed toward Leu523, Leu531, and Tyr355 without forming any H-bonds with the Ser530 or Tyr385 key residues.

Tumor necrosis factor (TNF)-α is one of the most common inflammatory mediators in different inflammatory diseases, such as rheumatic arthritis. The compound 2-chloro-N-(4-(2-morpholinoethoxy)phenyl)quinazolin-4-amine (99) was discovered by Pu et al. [66]. It inhibits TNF-α production (IC50 = 8.86 μmol/l in RAW264.7 cells), leading to promising inflammatory activity. In-vivo study revealed that compound 99 was a potent antiarthritic candidate as it enhanced the arthritic score, decreased the infiltration of inflammatory cells, and protected the joints from destruction ([Figure 46]).
Figure 46: Structures of novel 4-amino quinazoline derivatives.

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Furthermore, novel 4-amino quinazoline derivatives were synthesized. They were tested as anti-inflammatory agents in lipopolysaccharide (LPS)-induced macrophages [67] ([Figure 46]). The four most active derivatives 100a, 100b, 100c, and 100d showed inhibition of TNF-α and interleukin-6 release depending upon the used concentration. The results revealed that derivatives 100b and 100d, especially 100d, alleviated lung histopathological changes, inflammatory cell infiltration, and cytokine mRNA expression initiated by LPSs. In view of these results, this study proved that 100b and 100d could alleviate acute lung injury by in-vivo and in-vitro inhibition of the inflammatory response. Thus, it was indicated that various quinazolines could act as potential relieving agents in acute lung injury and serve as basic scaffolds in drug development and research.

A novel class of 2,3-dihydro-2-(substituted-phenyl)pyrazolo [5,1-b]quinazolin-9(1H)-ones was reported by Hussein et al. [68]. The new derivatives were examined for their anti-inflammatory activity using diclofenac sodium as a reference standard. The tested compound 101 showed remarkable potency when compared with the reference drug ([Figure 47]).
Figure 47: Structures of different quinazolone derivatives with anti-inflammatory activity.

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At the same time, Eweas et al. [69] designed and prepared new 2-pyridyl(3H)-quinazolin-4-one derivatives for anti-inflammatory evaluation. The whole evaluated compounds showed promising activity comparable to that of the standard drug indomethacin. Among them, compounds 102 and 103 revealed the most potent anti-inflammatory activity.

New quinazolin-4(3H)-one derivatives were prepared by Saravanan et al. [70] for anti-inflammatory evaluation. The derivatives that were substituted with halogen atoms, particularly those carrying trifluoromethyl groups, revealed potent anti-inflammatory activity. Among all tested compounds, trifluoromethyl analog 104 exhibited more potent activity compared with diclofenac ([Figure 47]).

Farag et al. [71] reported the synthesis of novel 3-(4-chlorophenyl or 4-fluorophenyl)-6-iodo-4-oxo-3,4-dihydroquinazoline derivatives carrying Schiff bases and various heterocyclic motifs such as oxazolone, imidazolidine, pyrazolidine, pyridine, and pyrimidine ([Figure 47]). The anti-inflammatory evaluation in chronic models showed that 3-(4-fluorophenyl)-2-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylimino)-methyl]-6-iodo-3H-quinazolin-4-one (105), which has –N = CH–pyrazoline moiety at C2 position and fluorophenyl at C3 position, produced the strongest anti-inflammatory activity. Other derivatives such as 106 and 107 incorporating –N = CH-substituted pyrazoline moieties at C2 positions also showed potent anti-inflammatory activity but slightly less than that of compound 105.

Al-Salahi et al. [72] prepared a novel set of 2-methylsulfanyl- [1, 2, 4]triazolo [1,5-a]quinazoline derivatives ([Figure 48]). The new analogs were tested as anti-inflammatory agents. The tested samples showed varying degrees of anti-inflammatory activity. Some compounds showed potential potent anti-inflammatory activity with respect to that of dexamethasone and the control, which varied from 75 to 86% inhibition, comparable to that of LPS-induced cells. Some others possessed moderate activity, with inhibition ranging from 50 to 70%. Overall, these results indicated that compounds 108112 are promising multipotent anti-inflammatory agents.
Figure 48: Structures of 2-methylsulfanyl-[1,2,4]triazolo[1,5-a]quinazoline derivatives.

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Zayed and Hassan [73] prepared novel analogs of 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones carrying sulfonamide moieties ([Figure 49]). The newly synthesized derivatives were examined as anti-inflammatory candidates using the carrageenan-induced hind-paw edema test. Ibuprofen was used as a reference standard. Among the screened compounds, 113 and 114 with aliphatic side chains showed higher activity than those bearing aromatic moieties. Compound 114 was found to be the most active one with a relative potency of 74% of the ibuprofen potency.
Figure 49: Structures of 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones.

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Anticonvulsant activity

The quinazoline ring system is considered the ‘master key’ in anticonvulsant therapy. It constitutes the basic scaffold of many common anticonvulsant drugs [74],[75]. Examples of the potent anticonvulsant drugs containing quinazoline core are mentioned in [Figure 50].
Figure 50: Some of the potent anticonvulsant drugs bearing the 4(3H)-quinazolinone ring.

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In medicinal chemistry, the 4(3H)-quinazolinone scaffold is considered one of the most important heterocycles for synthesis of various anticonvulsant agents. Many studies have reported that the attachment of a methyl group at position 2 and a substituted aromatic ring at position 3 of the 4(3H)-quinazolinone ring is essential for CNS depression and anticonvulsant activities. Novel 2, 3, 8-trisubstituted-4(3H)-quinazoline derivatives were prepared and assessed as antiepileptic agents, being compared with the reference drugs methaqualone and sodium valproate [76]. Compounds 2- [3,4-dihydro-2-methyl-3-(2-methylphenyl)-4-oxoquinazolin-8-yloxy]acetic acid hydrazide (115), ethyl-2-[2-(2-methyl)-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy) acetyl]hydrazincarboxylate (116), and methyl-2-[2-(2-methyl-3-(2-methylphenyl)-4(3H)-quinazolin-8-yloxy)acetyl]hydrazinecarbodithioate (117) ([Figure 51]) produced the strongest activity in this class with relatively low neurotoxicity. The resultant data showed that the most potent analogs could serve as basic templates for further optimization and development to obtain more potent anticonvulsant candidates.
Figure 51: Structures of novel 4(3H)-quinazolinone derivatives.

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Also, a new set of 2-aryl-6,7-methylenedioxy-3H-quinazolin-4-ones was prepared and examined for their antiepileptic activity. They are considered to be prototypes of the 2,3-benzodiazepine core structure, thus providing a rationale for compounds 118, 119, and 120 to demonstrate significant anticonvulsant and neuroprotective actions ([Figure 52]) [77].
Figure 52: Structures of novel 2-aryl-6,7-methylenedioxy-3H-quinazolin-4-ones.

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Also, Colotta et al.[78] prepared new 3-hydroxyquinazoline-2,4-diones carrying a trifluoromethyl group at quinazoline-C7 position and different functionalities at C6 position. Glycine (Gly)/N-methyl-D-aspartate receptor (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA), and kainic acid (KA) receptor binding data showed that the 7-trifluoromethyl moiety improved the affinity and selectivity toward AMPA and KA receptors compared with the 7-chlorine atom. In the new class, 6-(1, 2, 4-triazol-4-yl) derivative 121 ([Figure 53]) exhibited the most affinity and selectivity toward the AMPA receptor, displaying efficient anticonvulsant activity with decreasing neuronal damage [78].
Figure 53: Structure of the 6-(1,2,4-triazol-4-yl)-quinazoline derivative.

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According to the molecular docking results of compound 121, the quinazoline ring exhibited hydrogen bonding with iGluRs: Arg96, Thr91, and Pro89 at the AMPA receptor ([Figure 55]) and with Arg131, Thr126, and Pro124 at the Gly/NMDA receptor. The NH group of the compound acts as a proton donor toward the backbone C = O of Pro89, whereas the 2-carbonyl group accepts a hydrogen bond from the backbone –NH– of Thr91 at the AMPA receptor site. Moreover, both 2-carbonyl and 3-hydroxy groups interact with the side chain of Arg96. The triazole nucleus accepts a hydrogen bond from the Thr174 side chain.

A novel class of 1,9-disubstituted-8-chloro-pyrazolo [1,5-c]quinazoline-2-carboxylates was prepared by Varano et al.[79]. The binding affinities of the new derivatives toward AMPA, Gly/NMDA, and KA receptors were tested. The obtained data revealed that the attachment of 1,2-dicarboxylic acid groups and suitable substituted benzene moieties to the basic pyrazole-quinazolinone core (compounds 122) ([Figure 54]) was essential to obtain new selective candidates of AMPA receptor antagonistic action.
Figure 54: Structures of different pyrazolo[1,5-c]quinazolinone derivatives.

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At the same time, a class of new 3-[5-substitutedphenyl-1, 3, 4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones (compounds 123) ([Figure 55]) was synthesized by Jatav et al.[80]. The anticonvulsant activity evaluation exhibited that the derivatives bearing phenyl, p-chlorophenyl, and m-chlorophenyl substituents on the thiadiazole ring had promising antiepileptic potency in the MES screen. When tested for neurotoxicity, the derivative bearing a phenyl residue on the thiadiazole moiety displayed promising potency devoid of neurotoxicity.
Figure 55: Structures of 1,3,4-thiadiazole-quinazoline-4(3H)-one derivatives.

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The antiepileptic and inhibitory activity against the monoamine oxidase enzyme of different methaqualone analogs ([Figure 56]) was tested by Misra et al. [81]. It was observed that quinazolines possessing hydramide moiety had selective antiepileptic activity. The attachment of the 2-hydroxy-3,5-dichlorophenyl group at the Ar-moiety enhances the antiepileptic potency. At the same time, in the case of hydrazide analogs, the attachment of a chlorine atom at position 2 of the phenyl ring and a styryl residue at position 2 of the quinazolone ring also enhances the antiepileptic activity.
Figure 56: Structures of different methaqualone analogs.

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It has been noted that 6-chloro-3-(4-benzhydrazide)-2-(2′-chlorostyryl)-4-quinazolones (compounds 124) produced the strongest antiepileptic potency and produced 60% protection against Pentylenetetrazole (PTZ)-induced seizures in mice.

3-Hydroxy-quinazoline-2,4-diones (compounds 125) have been designed and synthesized by Catarzi et al.[82] ([Figure 57]). The affinity toward the AMPA receptor was assessed by the new quinazolinone derivatives. The data obtained showed that conjugation of a N3-nitrogen-containing heterocycle at position 8 of the basic backbone plays a very important role in inducing potency and selectivity toward the AMPA receptor. Also, the introduction of potent electron-withdrawing groups, such as chlorine atom, trifluoromethyl, or nitro substituents at position 7 of the quinazolinone heterocycle, enhanced the activity and selectivity toward the same target [82].
Figure 57: Structures of 3-hydroxy-quinazoline-2,4-dione derivatives.

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The novel derivative 5-phenyl- [1, 2, 4]triazolo [4,3-c]quinazolin-3-amine (126) was synthesized by Zheng et al.[83] ([Figure 58]). This derivative exhibited promising antiepileptic activity (ED50 = 27.4 mg/kg). Compound 126 exhibited clonic seizure inhibition by 30%, and absolute protection against the tonic seizures. It has been demonstrated that the antiepileptic potency of compound 126 was mediated by the γ-aminobutyric acid) system [83].
Figure 58: Structure of the [1,2,4]triazolo[4,3-c]quinazoline derivative.

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El-Azab and El-Tahir [76] have synthesized new 7-substituted-4(3H)-quinazolinone compounds [76]. The new derivatives were evaluated as anticancer and anticonvulsant agents. Compounds 127, 128a,b, and 129a,b showed remarkable antiepileptic activity with lower neurotoxicity compared with the standard drugs methaqualone and valproate ([Figure 59]). The most potent agents were selected for further examinations at various concentrations for quantification of their antiepileptic potency. The compounds exhibited ED50 values of 0.74, 0.31, 0.35, 0.70, and 0.40 mmol/kg, respectively. Methaqualone and valproate showed ED50 values of 1.40 and 1.5 mmol/kg, respectively. Interestingly, ED50 values of the tested agents appeared to be lower than those of the reference drugs at the same molar concentrations. The data revealed that these derivatives might be valuable scaffolds for further design and improvement in order to obtain more potent agents [76].
Figure 59: Structures of 7-substituted-4(3H)-quinazolinone derivatives.

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Kadi et al.[84] produced a new class of 2-mercapto-3-(4-chlorophenyl)-4-oxo-6-iodoquinazolines ([Figure 60]). The antiepileptic potency of the new derivatives was evaluated using the PTZ seizure threshold test. Compounds 130–133 showed significant anticonvulsant activity with complete disappearance of seizures during the course of the assay. According to the obtained data, these compounds showed potent CNS depressant effects, accompanied by sedation and hypnosis [84].
Figure 60: Structures of 2-mercapto-3-(4-chlorophenyl)-4-oxo-6-iodoquinazolines.

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New derivatives of the quinazolinedione nucleus conjugated with sulfonamide moieties were prepared by Orain et al.[85]. The newly synthesized compounds appeared as competitive AMPA receptor antagonists with better characteristics, particularly compound 134 ([Figure 61]).
Figure 61: Structure of the quinazolinedione-sulfonamide derivative.

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The central skeleton of 134 formed a favorable π–π stacking with Tyr450 and hydrogen bonds with the residues Pro478, Thr480, and Arg485. Additional hydrogen bonds were also formed by the derivative 134 with Thr686 and Glu402 (NH amide), which might be responsible for higher affinity [85].

Quinazoline-2,4-diones attached to sulfonamide groups have been prepared as a new set of effective competitive AMPA receptor antagonists of strong receptor affinity and significant oral in-vivo activity. Compound 135 ([Figure 62]) showed nanomolar receptor affinity [86].
Figure 62: Structure of the quinazoline-2,4-dione-sulfonamide derivative.

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Koller et al.[86] constructed the human receptor hGluA2 and successfully cocrystallized it with the antagonist 135. An X-ray structure investigated the binding mode of the two chemo types. Compound 135 was directed such that a favorable p-stacking with Tyr450 occurred and then formed the hydrogen bond. The sulfonamide nitrogen reacts with H3Np–Arg485, revealing that this nitrogen was negatively charged, which led to a strong Coulomb interaction. The ring –HN group exhibited significant hydrogen bonding interaction with the carbonyl group of Pro478. The imidazole moiety formed a hydrogen bond with the side chain hydroxyl group of Thr686, and the adjacent nitro substituent made water-mediated contact with Tyr405 and Thr707.

Patents for quinazolines as antiepileptics were recently granted at World Intellectual Property Organization (WIPO), United States Patent and Trademark Office (USPTO), and European Patent Applications and Specifications related to quinazolines. These patents proved that quinazolines are very useful in seizure disorders. Floersheim et al.[87] claimed that quinazolines are effective pharmaceuticals in the treatment of epilepsy, especially in partial seizures (simple, complex, and partial evolving to secondarily generalized seizures) and generalized seizures [absence (typical and atypical), myoclonic, clonic, tonic, tonic–clonic, and atonic]. Further, the compounds of the general chemical structures 136 and 137 ([Figure 63]) were combined with other drugs to be more active in various conditions such as epilepsy. They could be combined with other anticonvulsants like barbiturates, benzodiazepines, carboxamides, hydantoins, succinimides, valproic acid, and other AMPA antagonists.
Figure 63: Chemical structures of different quinazoline derivatives. R1 = alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, araalkynyl, heteroaralkyl, cyanoalkyl, azidoalkyl, alkoxyalkyl; R5 and R6 = hydrogen, halogen, haloalkyl, heterocyclic, heteroaryl, nitro, cyano, amino, thiol, carboxy, carbonylamido, thioalkoxy; R6 and R7 taken together to form a five or six membered carboxylic or heterocyclic rings; R8 = optionally substituted lower alkyl. X = O or S; Y = aryl or heteroaryl; n=z = 0 or 1.

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Floersheim et al.[87] documented that quinazolines were valuable inhibitors of voltage-gated sodium channels and calcium channels. The invention also produced suitable quinazoline pharmaceuticals to treat different neurodegenerative diseases including seizure disorders. Also, they decreased the severity of trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, neurodegenerative disorders, and pychiatric disorders such as anxiety, depression, and myotonia ([Figure 64]).
Figure 64: Chemical structures of quinazolines as inhibitors of ion channels. R1 and R2 are each independently an optionally substituted group selected from hydrogen C1–6 aliphatic. CY is a 5–7-membered monocyclic aryl ring or an 8–10-membered bicyclic aryl ring having 0–3 heteroatoms alkyl. R3 comprises alkylidend side chains.

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Treatment of Alzheimer's disease

The overproduction of β-amyloid (Aβ) peptide and its extracellular deposition is the most important factor associated with the etiology of Alzheimer's disease [88]. Elkamhawy et al. [88] had synthesized a novel class of quinazoline-urea derivatives. Their blocking potency against Aβ peptide was assessed. Seven compounds, 139ag ([Figure 65]), displayed higher potency compared with the standard cyclosporin A. MTT assay showed that the new candidates had excellent cellular viability. The quinazoline-urea compound 139 g, as the most active agent, produced activity that was two-fold higher than that of cyclosporin A, thus giving new direction for the design and synthesis of novel Aβ peptide blockers.
Figure 65: Structures of novel quinazoline-urea derivatives.

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Xanthine oxidase inhibitory activity

Xanthine oxidase (XO) is a well-characterized druggable target in the treatment of diseases due to increased uric acid levels, such as hyperuricemia and gout, because of its significant role in catalytic oxidative hydroxylation of hypoxanthine and xanthine to produce uric acid. Further, XO is also associated with various diseases such as inflammation, metabolic disorders, cellular aging, reperfusion damage, atherosclerosis, hypertension, and carcinogenesis as it generates superoxide anions, H2O2, and highly reactive species (reactive oxygen species) during the catalytic process [89]. Therefore, the selective inhibition of XO leads to therapeutical relief from gout, cancer, inflammation, and oxidative damage [89]. Kumar et al. [89] designed and synthesized pyrazolo [1,5-c]quinazoline derivatives (compounds 140a–e) ([Figure 66]) to be tested as in-vitro XO inhibitors. The compounds 140d, 140e, and 140c significantly inhibited XO. The most potent XO inhibitor and free radical scavenger was compound 140d, when compared with allopurinol. The molecular docking of 140d into the XO active site highlighted its mode of binding and important interactions such as hydrogen bonding and π–π stacking with amino acid residues like Ser876, Thr1010, Phen914, Phe1009, and Phe649.
Figure 66: Structures of novel pyrazolo[1,5-c]quinazoline derivatives.

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Immunotherapeutic activity

Toll-like receptors (TLRs) are critical components of the innate immune system that regulate immune recognition in part through NF-κB activation. A human cell-based high-throughput screen exhibited substituted 4-aminoquinazolines to be small-molecular-weight activators of NF-κB. Synthetic modifications of the quinazoline scaffold at the two and four positions led to the formation of the hit compound 141, which activated the interferon signaling pathway resulting in type I interferon production [90]. The attachment of different moieties such as bromine, chlorine, and methyl at the orthoposition of the phenyl ring enhanced the immunological potency ([Figure 67]). Computational studies showed that the 4-aminoquinazoline compounds 142 bound primarily to human MD-2 in the TLR4/MD-2 complex. These molecules, which preferentially stimulate the human immune cells, may be valuable adjuvants or immunotherapeutic agents [90].
Figure 67: Structures of novel substituted 4-aminoquinazoline derivatives.

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Clinical transplantation is a routine procedure, and its success is based on the matching of the major histocompatibility complex, on immune suppressive drugs, and on technical skills. Most transplants need immunosuppressants, which might be toxic, leading to cancer and infection. Induction of specific tolerance, which would inhibit the response to the graft without compromising host defense, is now characterized as the ‘holy grail’ of immunology. Sagiv-Barfi et al. [11] synthesized a new class of quinazoline derivatives that were examined as inhibitors of T-cell proliferation. N-p-tolyl-2-(3, 4, 5-trimethoxyphenyl)quinazolin-4-amine (143) ([Figure 68]) appeared to be the most potent analog inhibiting the growth of T cells with IC50 in the submicromolar range.
Figure 68: N-p-tolyl-2-(3,4,5-trimethoxyphenyl)quinazolin-4-amine.

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5-Hydroxy tryptamine2A receptor antagonistic activity

The 5-hydroxy tryptamine (5-HT)2A receptor is a G-protein-coupled receptor that generally mediates excitatory neurotransmission. One of the most fundamental biological functions of the 5-HT2A receptor is the regulation of dopamine release in three dopaminergic pathways. 5-HT2A is involved in a wide array of etiological processes including schizophrenia, depression, anxiety, migraine, hallucinations, insomnia, and addiction [91]. Nevertheless, 5-HT2A antagonists have joined with D2 dopamine antagonists as the most frequently used atypical antipsychotic agents. A new class of compounds carrying the quinazoline nucleus was prepared and assessed as new effective 5-HT2A receptor ligands [91]. Compound 144a ([Figure 69]) was particularly attractive as 5-HT2A and was discovered by pharmacophore-based virtual screening against the 5-HT2A receptor, followed by biological assays. Compound 144e is composed of a quinazoline core, an arm (piperazinyl-ethanol) and a tail (dimethoxy-aniline). Molecular modeling studies used this structural model to design and form a novel set of N-(substituted phenyl)-2-(piperazin-1-yl)quinazolin-4-amine derivatives (compound 144b–e). Compound 144e showed relatively high binding affinity to the 5-HT2A receptor (Ki = 14.04 nmol/l), as well as antagonist activity (IC50 = 1.66 μmol/l). This is the first time that quinazoline analogs have been discovered to be highly effective and selective ligands for the 5-HT2A receptor [91]. Investigations of more potent and selective quinazoline derivatives are required for their practical and therapeutic applications in the future.
Figure 69: Structures of piperazine–quinazolines.

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Antidepressant activity

New 4-(substituted-phenyl)tetrazolo [1,5-a]quinazolin-5(4H)-ones ([Figure 70]) were designed and prepared to be tested as antidepressant agents [92]. The biological assays revealed that derivatives 145a, 145b, and 145c at a dose of 50 mg/kg significantly decreased the immobility time of mice in the forced swimming test. The most potent derivative was 4-(p-tolyl)tetrazolo [1,5-a]quinazolin-5(4H)-one (145c), which reduced the immobility time by 82.69% at 50 mg/kg. This result was approximately equivalent to the antidepressant effect of fluoxetine. The underlying mechanisms of these compounds might be due to the regulation of the brain monoamine neurotransmitter homeostasis, based on the detected increased levels of noradrenaline and 5-HT and the reduced content of monoamine oxidase enzyme in mouse brain tissues.
Figure 70: Structures of tetrazolo[1,5-a]quinazolin-5(4H)-one derivatives.

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Antidiabetes mellitus type 2

GPR119 is a G-protein-coupled receptor predominantly expressed in pancreatic β cells and intestinal enteroendocrine cells. GPR119 agonists enhance insulin secretion in vitro and reduce the elevated blood glucose level in vivo. In addition, they enhance the secretion of incretin (GLP-1 and GIP). Accordingly, GPR119 agonists were recently considered as important targets for the treatment of type 2 diabetes and obesity by controlling glucose homeostasis [93]. New derivatives of 2,4-disubstituted quinazolines incorporated with heterocyclic alcohols and azabicyclic amine groups ([Figure 71]) have been synthesized and tested as GPR119 agonists. It has been shown that the derivatives carrying (2-fluoro-4-methylsulfonyl)phenylamino and azabicyclic amine groups with N-Boc (146a–c) have promising EC50 values. The obtained results suggested that the steric bulkiness of the attached groups enhanced the bioactivity, while the configuration (endo vs. exo) did not produce a remarkable effect. Better bioactivity was obtained by the electronic effects of the conjugated groups at position 2 of the benzene ring as well as the N-Boc group of azabicyclic amines. Further SAR studies to obtain more effective GPR119 agonists carrying different heterocyclic scaffolds are under progress [93].
Figure 71: Structures of novel 2,4-disubstituted quinazoline derivatives.

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Antiobesity activity

Melanin-concentrating hormone is a 19-amino-acid cyclic neuropeptide expressed predominantly in the lateral hypothalamus and zona incerta. The pivotal roles of melanin-concentrating hormone and the melanin-concentrating hormone receptor 1 (MCHR1) in the body weight and feeding regulation ensure the hypothesis that MCHR1 antagonists constitute new targets for the treatment of obesity [94]. The quinazoline compounds 147, 148, and 149 ([Figure 72]) were characterized as potent MCHR1 antagonists. It has been found that the efficacy of compound 147a could be obtained with a safe cardiovascular profile.
Figure 72: Structures of novel 7-substituted-quinazoline derivatives.

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Bronchodilatory activity

A series of quinazoline-heterocyclic derivatives were prepared analogs to vasicinone (vasicine and vasicinone are major quinazoline alkaloids isolated from Justicia adhatoda L. and are known to have a moderate bronchodilatory effect), in which the vasicinone C-ring was replaced with the alkyl chain terminated by tertiary amine [95]. The new derivatives (150) ([Figure 73]) displayed bronchodilatory effect at low micromolar concentrations (ED50 = 0.178–1.90 mmol/l, ED50 of theophylline 2.090 mmol/l, ED50 of vasicinone 2.864 mmol/l) on isolated rat trachea, and low toxicity both on Balb/c3T3 mouse fibroblast cells and in mice.
Figure 73: Structures of quinazoline-heterocyclic derivatives analogous to vasicinone alkaloids.

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Antimicrobial activity

A new series of 6,7-bis(arylthio)-quinazoline-5,8-dione and furo [2,3-f]quinazolin-5-ol derivatives were prepared and evaluated as in-vitro antifungal agents against Candida spp., Aspergillus spp., and Cryptococcus neoformans. Among them, 2-amino-4-arylthio-5-hydroxyfuro [2,3-f]quinazoline derivatives (151a,b) ([Figure 74]) exhibited complete growth inhibition of the tested Candida spp. and Aspergillus spp. at an minimum inhibitory concentration (MIC) level of 12.5 μg/ml. The obtained data suggested that furo [2,3-f]quinazolines could be promising antifungal agents [96].
Figure 74: Structures of 5-hydroxyfuro[2,3-f]quinazoline derivatives.

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Maurya et al. [97] have synthesized various substituted 5,6-dihydro-8 methoxybenzo[h]quinazolin-2-amine derivatives in good yields, following an efficient method. Compounds 152a, 152b, and 152c ([Figure 75]) exhibited significant antitubercular activity at MIC values of 50, 100, and 50 μmol/l, respectively, in an in-vitro assay against the Mycobacterium tuberculosis H37Rv strain.
Figure 75: Structures of 5,6-dihydro-8-methoxybenzo[h]quinazolin-2-amine derivatives.

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The 2-mercaptoquinazoline compound (153) exhibits antifungal activity through the physiological pathway and through cytotoxicity ([Figure 76]). It is hypothesized that it first attacks the cell wall and destroys the fungal cell, exerting its fungicidal effect through cytotoxicity. Second, it directly prevents energy metabolism, protein biosynthesis, and enzyme activity and indirectly prevents the building of the cell architecture through the physiological pathway [98].
Figure 76: Structure of the 2-mercaptoquinazoline derivative.

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A new set of 1-methyl-3-substituted quinazoline-2,4-dione derivatives were designed and prepared ([Figure 77]) [99]. They were evaluated as chitin synthase inhibiting agents and as antifungal agents. Results showed that compounds 154a–d had a strong inhibitory effect against chitin synthase. Compound 154b showed the highest activity of IC50 = 0.08 mmol/l, whereas polyoxin B as a standard drug exhibited IC50 of 0.18 μmol/l.
Figure 77: Structures of 1-methyl-3-substituted quinazoline-2,4-dione derivatives.

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Plasmodium, the parasite that infects humans with malaria, multiplies in the liver and is then released into circulating erythrocytes. Therefore, the erythrocyte cell membrane has an essential role in the potency of different antimalarial drugs or in inducing resistance against them. The antiplasmodial activity of N6-(4-methoxybenzyl)quinazoline-2, 4, 6-triamine (155) is produced in human erythrocytes and on their cell membranes [100] ([Figure 78]).
Figure 78: Structure of quinazoline-2,4,6-triamine derivative.

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Antiviral activity

Chen et al. [101] identified several indole-based quinazoline derivatives with antihepatitis activity ([Figure 79]). SAR studies of the indole substituents optimized the potency and protein kinase (PK) properties. Optimization of C4, C5, and C6 substituents led to the formation of 4,5-furanylindole as the best core for antihepatitis activity. The C2 carboxylic acids exhibited better PK properties than the corresponding acylsulfonamides. Accordingly, the derivative (156) was considered as a promising lead with high activity. Leivers et al. [102] discovered small-molecule type III phosphatidylinositol 4-kinase α (PI4KIIIα) inhibitors as antihepatitis C virus (anti-HCV) agents. They have also described the methods for their preparation and SARs associated with their biological inhibition of PI4KIIIa and HCV replication. The biological data revealed that the pyridine-based quinazolinone derivative (157) has high selectivity for PI4KIIIa and potently inhibits HCV replication in vitro.
Figure 79: Structures of indole/pyrido-based quinazoline derivatives.

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A new set of (1E,4E)-1-aryl-5-[2-(quinazolin-4-yloxy) phenyl]-1,4-pentadien-3-one derivatives has been prepared by Luo et al.[103]. The derivatives were tested as antiviral agents. Antiviral bioassays proved that most of the compounds exhibited promising in-vivo antiviral bioactivity against the tobacco mosaic virus and the cucumber mosaic virus at 500 mg/ml. Also, it has been revealed that the compounds (158a–c) ([Figure 80]) could possess appreciable protective bioactivities on tobacco mosaic virus ex vivo by ∼50% (EC50) at 257.7, 320.7, and 243.3 mg/ml.
Figure 80: Structures of (quinazolin-4-yloxy)phenyl-1,4-pentadien-3-one derivatives.

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Antitrypanosomatid and antiplasmodial activity

A novel set of 2, 4, 6-triaminequinazoline derivatives has been designed and synthesized as potential trypanocidal, leishmanicidal, and antiplasmodial agents [104]. The new derivatives were rationalized using docking studies of the dihydrofolate reductase (from Trypanosoma cruzi, Leishmania major, and Plasmodium vivax) and pteridine reductase (from T. cruzi and L. major) architectures. All of the newly synthesized analogs were examined in vitro against both bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and promastigotes of Leishmania mexicana (MHOM/BZ/61/M379 strain) and also for cytotoxicity using the Vero cell line. The derivatives (159b–d) ([Figure 81]) were the most active agents against T. cruzi, exhibiting better activity compared with standard drugs nifurtimox and benznidazole. Also, the analogs (159b–e) exhibited the strongest potency against L. mexicana, compared with glucantime (the reference drug). In the cytotoxicity assay, protozoa were more susceptible than Vero cells. In vivo, the Plasmodium berghei assay (ANKA strain) showed that the analogs (159a–e) had more potency than chloroquine and pyrimethamine (reference drugs) upon oral administration. The antiprotozoal potency of these compounds represents an important point in therapeutical chemistry in the treatment of Chagas’ disease, leishmaniosis, and malaria.
Figure 81: Structures of 2,4,6-triaminoquinazoline derivatives.

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Antileishmanial activity

The derivative N6-(ferrocenmethyl)quinazolin-2, 4, 6-triamine (160) is one of a set of quinazoline-2, 4, 6-triamines ([Figure 82]) that were prepared and assessed in vitro against L. mexicana[104]. It displayed potency on promastigotes and intracellular amastigotes stages of the parasite besides its drawbacks in human tissues. Interestingly, antiparasitic effect is mainly related to the presence of the ferrocene group. This moiety affords important characteristics to the molecule, primarily as a result of the readily oxidized iron atom. According to various studies, the ferrocene group can exert its effect through redox reactions by means of its ability to exert reactive oxygen species, principally the hydroxyl radicals. Additionally, the quinazoline-2,4-diamine scaffold is required for further biological activity.
Figure 82: Structures of quinazoline-2,4,6-triamine derivative.

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Various quinazoline derivatives of miscellaneous activities

Amin et al. [105] synthesized a new class of spiro[(2H,3H)quinazoline-2,1′-cyclohexan]-4(1H)-one analogs as PARP-1 inhibitors. Twenty-one derivatives that exhibited the best fit to the target enzyme according to the docking study were selected to assess their in-vitro cytotoxic potency. It has been found that most of the synthesized quinazoline derivatives exhibited effective antiproliferative activity against breast carcinoma cell lines and showed effective inhibitory effect on the target PARP-1 enzyme (compounds 161167) ([Figure 83]).
Figure 83: Structures of spiro[(2H,3H)quinazoline-2,1′-cyclohexan]-4(1H)-one derivatives.

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Also, a series of spiroquinazoline-2,1′-cyclohexan-4(1H)-one derivatives conjugated to various aromatic and/or heterocyclic ring systems such as benzenesulfonamide, pyrazoline, oxazoline, pyrimidin-2-thione, 2-oxo(imino)pyridine, imidazoline, and thiazolidinone have been designed and synthesized as anti-inflammatory and analgesic agents [106]. It has been found that the tested derivatives exhibited dual pharmacological activities with superior gastrointestinal safety profile compared with the reference drug indomethacin ([Figure 84]).
Figure 84: Structures of novel derivatives of spiroquinazoline-2,1′-cyclohexan-4(1H)-one derivatives.

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Recently, a new set of hybrids bearing N-phenylquinazolin-4-amine and hydroxamic acid moieties (compounds 172) were synthesized and identified as dual VEGFR-2/HDAC (histone deacetylase-like protein) inhibitors with IC50 ranging in the nanomolar levels [107] ([Figure 85]).
Figure 85: Structures of novel N-phenylquinazolin-4-amin-hydroxamic acid hybrids. HDAC, histone deacetylase; VEGFR-2, vascular endothelial growth factor receptor 2.

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A novel class of 7- or 8-substituted 4-morpholine-quinazoline compounds was designed and prepared. The inhibitory effects of the new derivatives against the PI3Kα enzyme and seven tumor cell lines, PC-3, DU145, MCF-7, BT474, SK-BR-3, U937, and A431, were examined in vitro. The derivative 173 exhibited high PI3Kα inhibition potency (IC50 = 4.2 nmol/l) and promising cancer activity. Also 173 displayed a remarkable inhibitory action against the PI3K/Akt/mTOR pathway as a potent PI3K inhibitor and anticancer agent [108],[109] ([Figure 86]).
Figure 86: 7-Substituted-4-morpholine-quinazoline derivatives.

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  Conclusion and perspectives Top


Drug discovery and improvement of existing drugs has a pivotal role in the progress of therapeutic chemistry. Significant attention is being diverted to the development of the molecular architecture of heterocyclic compounds in (bio)organic chemistry. In this review, we have introduced a wide range of novel, effective, mild, and simple routes of synthesis to gain various substituted quinazoline and quinazolinone derivatives through readily available and cheap starting materials. Several strategies including metal-catalyzed reactions, MW irradiation, and conventional heating methods have been successfully employed to achieve these diversely decorated skeletons, which are of significant importance in pharmaceutical and agrochemical industries. This review also discusses numerous biological targets with significant bioactivities. Several quinazoline-based and quinazolinone-based drugs have already made their way to clinics and are being successfully used against various disorders. The SAR showed that obtaining the required biological potency for the synthesized compounds depends on the selection of a suitable substitution pattern, including electron-donating and electron-withdrawing, as well as some heterocyclic moieties, on the basic backbone. Furthermore, because of the simplicity of synthetic methods enabling the construction of core scaffolds of many marketed drugs, we hope to see further research in the design of novel functionalized quinazoline and quinazolinone derivatives, with exploitation of their biological activities in diverse ways. Chemical and biological studies should be continued on these scaffolds with the aim to obtain novel drugs with various biological activities of high selectivity and potency and devoid of the side effects of the parent drugs.

Acknowledgements

The authors are grateful to National Research Centre, Cairo, Egypt.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

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