Recent advances in the structural library of functionalized quinazoline and quinazolinone scaffolds: Synthetic approaches and multifarious applications

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European Journal of Medicinal Chemistry 76 (2014) 193e244

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European Journal of Medicinal Chemistry

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Recent advances in the structural library of functionalized quinazolineand quinazolinone scaffolds: Synthetic approaches and multifariousapplications

Imtiaz Khan, Aliya Ibrar, Naeem Abbas, Aamer Saeed*

Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan

a r t i c l e i n f o

Article history:Received 20 December 2013Received in revised form4 February 2014Accepted 6 February 2014Available online 7 February 2014

Keywords:HeterocyclesSynthetic methodsInhibitorsQuinazolinesQuinazolinonesBiological activities

* Corresponding author.E-mail address: [email protected] (A. Saeed

http://dx.doi.org/10.1016/j.ejmech.2014.02.0050223-5234/� 2014 Elsevier Masson SAS. All rights re

a b s t r a c t

Drug development has been a principal driving force in the rapid maturation of the field of medicinalchemistry during the past several decades. During this period, the intriguing and challenging moleculararchitectures of nitrogen-containing heterocycles with potential bioactive properties have receivedsignificant attention from researchers engaged in the areas of natural product synthesis and heterocyclicmethodology, and constituted a continuous stimulus for development in bio(organic) chemistry. In thisperspective, the current review article is an effort to summarize recent developments in the environ-mentally benign synthetic methods providing access to quinazoline and quinazolinone scaffolds withpromising biological potential. This article also aims to discuss potential future directions on thedevelopment of more potent and specific analogues for various biological targets.

� 2014 Elsevier Masson SAS. All rights reserved.

1. Introduction

Heterocycles occupy a central position in organic chemistry [1e3], and are of particular interest and significant importance in thesearch for new bioactive scaffolds in both the agrochemical andpharmaceutical industries. Indeed, with particular reference to thepharmaceutical industry, heterocyclic motifs are especially preva-lent with over 60% of the top retailing drugs containing at least oneheterocyclic nucleus as part of the overall topography of the com-pound [4]. In addition, the exploitation of a small molecule to adesirable extent is a valuable contribution in the field of syntheticorganic and medicinal chemistry [5]. In this context, nitrogenheterocycles in particular exhibit diverse biological and pharma-cological activities due in part to the similarities with many naturaland synthetic molecules with known biological activity [6].Furthermore, compounds that contain heterocyclic moieties oftenexhibit improved solubilities and can facilitate salt formationproperties, both of which are known to be important for oral ab-sorption and bioavailability [7].

).

served.

Quinazoline 1 is 1,3-diazanaphthalene. It is also known as 5,6-benzopyrimidine or benzo[a]pyrimidine, or phenmiazine [8],and its 4-oxo derivative is called 4(3H)-quinazolinone 2 [9e11](Fig. 1).

Quinazoline and quinazolinone derivatives have attracted sig-nificant attention due to their diverse pharmacological activitiessuch as antimalarial [12], antimicrobial [13], anti-inflammatory[14], anticonvulsant [15], antihypertensive [16], anti-diabetic [17],cholinesterase inhibition [18], and anticancer activities [19].Moreover, several of these compounds like 3e7 and TMQ, exhibiteddihydrofolate reductase inhibition [20] (Fig. 2), and also used askinase inhibitors [21] such as gefitinib, erlotinib, caneratinib,dacomitinib, afatinib, vandetanib, ispinesib and compounds 8 and 9(Fig. 3). Some quinazoline derivatives interact with tubulin [22] andinterfere with its polymerization, others act by modulating aurorakinase activity [23] or have an effect in critical phases in the cellcycle [24] or act as apoptosis inducers [25].

Quinazolinone and their derivatives [26] are also building blockfor approximately 150 naturally occurring alkaloids isolated from anumber of families of the plant kingdom, frommicroorganisms andanimals (Fig. 4). Some of the compounds incorporating quinazoli-none motif like raltitrexed, thymitaq and compounds 10 and 11possess antitumor activities [27] (Fig. 5).

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Fig. 1. Chemical structures of quinazoline 1 and 4(3H)-quinazolinone 2.

I. Khan et al. / European Journal of Medicinal Chemistry 76 (2014) 193e244194

Quinazolines also exhibit a variety of biological functions likecellular phosphorylation inhibitors [28], ligands for benzodiazepineand GABA receptors in the central nervous system [29] and some ofthem have acted as DNA binding agents [30]. They have also shownto possess effective a-adrenergic blocking activity. Moreover, thesederivatives are core motifs of prazosin [31], bunazosin [32], anddoxazosin [33], useful medicines for antihypertensives. Some otherdrugs like proquazone and fluproquazone possess non-steroidalanti-inflammatory potential, afloqualone as muscle relaxant, anddiproqualone with sedative analgesic effects. KF31327 was devel-oped as a heart disease remedy and an impotence medicine [34]. Ina recent report, 3,4-dihydroquinazoline derivatives have beenfound to possess excellent T-type calcium channel blocking activity[35] (Fig. 6).

A vast number of quinazoline derivatives have been synthesizedto provide synthetic drugs and to design more effective medicines.There are a number of reviews [36] and monographs [37] on qui-nazoline and quinazoline alkaloids. But, owing to the number ofpublications reporting an extremely high output of results, therehas been no formal collection of recent advances encompassing thesynthetic methods through which these heterocycles (quinazolinesand quinazolinones) can be accessed, along with diverse biologicalprofile which they possess. So, in corollary of these fascinatingfindings as well as part of a programme aimed at finding hetero-cyclic structures with various pharmacological properties [38], wehave targeted the libraries of these novel heteroaromatic scaffoldswith broad spectrum of biological actions. The purpose of this re-view is to demonstrate that quinazoline and quinazolinone de-rivatives are privileged motifs which can be accessed through avariety of synthetic efforts/methodologies starting from cheap andreadily available starting materials, and are core structures found invarious commercial drugs.

Fig. 2. Structures of lead a

2. Progress in synthetic methods

In the past decade, a variety of synthetic methods have beenemployed for the preparation of functionalized quinazoline andquinazolinonemotifs and the level of interest in the current domainis clearly shown by the number of publications reporting anextremely high output of results as well as the presence of thesescaffolds in numerous marketed medicines as core structures. Thesubject matter of current review are aimed at providing acomprehensive overview of recent (2013) practical, extremelymild,and operationally simple methodologies used to construct quina-zoline and quinazolinone skeletons of pharmaceutical as well asagrochemical interest.

Fu and co-workers [39] developed an easy and efficient methodfor the synthesis of pyrazolo[1,5-c]quinazolines 13 via one-pot two-step process involving readily available substituted 1-(2-halophenyl)-3-alkylprop-2-yn-1-ones 12, hydrazine hydrochlo-ride and amidine hydrochlorides under mild conditions (Scheme1). With the optimized conditions in hand, the substrate scopewas examined using inexpensive CuI as a catalyst which affordedthe corresponding pyrazolo[1,5-c]quinazolines in good to excellentyields. This novel method affords a new strategy for the construc-tion of diverse and useful N-fused heterocyclic compounds forcombinatorial and medicinal chemistry.

Pal and co-workers [40] were able to develop an elegant, ver-satile, rapid and a new one-pot Cu-mediated synthetic methodol-ogy for the assembly of six membered fused N-heterocyclic ring,5H-isoquinolino[2,3-a]quinazoline-5,12(6H)dione 16 (Scheme 2).The starting material 14 was prepared via amide bond formationbetween 2-halo (het)aryl carboxylic acid chloride and 2-amino(het)aryl carboxylate ester which was coupled with ethyl cyanoa-cetate 15 to afford the required compound. The scope of thisdomino reaction was also examined which revealed that a diversevariety of substituents like alkynyl, phenyl, 2-thienyl or NO2 arecompatible under optimized conditions providing access to targetcompounds in good to excellent yields.

Menéndez and co-workers [41] described an efficient, user-friendly, one-pot synthetic protocol involving the combination ofMCR methodology and microwave heating affording 5,6-dihydroquinazolin-4-ones 23 (Scheme 3). The reaction involvesreadily available materials such as chalcones 17, 1,3-dicarbonylcompounds 18, butylamine 19, ammonium formate and form-amide via intermediate anthranilate derivatives 20, 21 and 22.

ntifolate compounds.

Fig. 3. Chemical structures of kinase inhibitors.

I. Khan et al. / European Journal of Medicinal Chemistry 76 (2014) 193e244 195

Furthermore, an efficient method for the aromatization of thedihydroquinazolinones was also developed, based on a microwave-assisted halogenationeelimination sequence in the presence of N-bromosuccinimide (NBS).

Wu and co-workers [42] demonstrated a palladium-catalyzedreaction of 2-iodoarylcarbodiimide 24, phosphite 25 and isocyanide26, affording4-imino-3,4-dihydroquinazolin-2-ylphosphonates27 inmoderate to goodyields (Scheme4). Threebonds are formed inaone-pot procedure and the tandem process includes nucleophilic attack,isocyanide insertion, and CeN coupling. 2-Iodoarylcarbodiimideswith both alkyl and aryl substituents were found to be good

Fig. 4. Structures of alkaloids incorporating title frameworks.

substrates for this transformation. On the other hand, a variety ofdipropyl phosphites and isocyanides were also workable.

Zhou and co-workers [43] developed a one-pot synthesis of 2-substituted quinazolines 30 between 2-aminobenzylamines 28and aldehydes 29 via iridium-catalyzed hydrogen transfers usingstyrene as a hydrogen acceptor (Scheme 5). Both aliphatic and ar-omatic aldehydes were reacted with 2-aminobenzylamines toafford the corresponding quinazolines 30 in moderate yields. Aro-matic aldehydes with either electron-withdrawing or electron-

Fig. 5. Structures of lead antitumor agents.

Fig. 6. Structures of marketed drugs incorporating title skeletons.


donating groups showed that the yields were not affected signifi-cantly. The use of benzyl alcohol 31 instead of benzaldehyde alsosuccessfully gave a quinazoline product 32 in moderate yield.

The desired and efficient synthesis of quinazolines 34 and 35was achieved by Zhang and co-workers [44] from amidines 33 in a

Scheme

Scheme

variety of solvents through direct oxidative amination of NeHbonds and methyl C(sp3)eH bonds followed by intramolecular CeCbond formation reactions under Cu catalysis (Scheme 6). Thismethod has been found to be very attractive as it involves readilyavailable amidines as substrates together with the high selectivity

1.

2.

Scheme 3.


of the annulation towards C(sp3)eH bonds. The annulated productswere obtained in good to excellent yields.

Chen and co-workers [45] demonstrated an interesting andefficient one-pot approach to multiple substituted quinazolines 38with diaryliodonium salts 36, and two nitriles 37 (Scheme 7). Thereactions are applicable to two different nitriles to give a regio-selective product. This process also enabled great flexibility of thesubstitution patterns on quinazolines. A range of functionalizeddiaryliodonium salts with various substitution patterns have been

Pd(OAc)2 (10 mol%)dppf (10 mol%)FeCl3 (10 mol%)

Cs2CO3, toluenereflux

R1 = H, Me, ClR2 = Ph, Bn, 4-Me-C6H4, 2-R3 = Et, i-PrR4 = t-Bu, n-Bu, cyclohexyl

I

NCNR2

R1

PO

OR3HOR3

R4 NC

R24

25 26

Scheme

found as competent partners for the construction of quinazolineframework.

Yan et al. [46] reported an efficient and simple procedure for theconstruction of 2-aryl-4-aminoquinazoline library 41 starting frompolyhalo isophthalonitriles 39 with amidine hydrochlorides 40under basic conditions with good yields (Scheme 8). To explore thescope and limitations of cyclocondensation reactions, the polyhaloisophthalonitriles and a series of amidine hydrochlorides wereused as substrates in this procedure. The results revealed that

I-C6H4, n-Bu, cyclohexyl

, 2,6-diMe-C6H3

N

NR2

PO(OR3)2

1

NR4

27

Fe

P

PPh

Ph

Ph

Ph

dppf37-78%

4.

Scheme 5.

Scheme 6.

Scheme 7.


amidine hydrochlorides with various substituents were all goodsubstrates for the cyclocondensation reaction.

Wang et al. [47] developed a concise method for the preparationof tryptanthrins 44 from indoles 42 under mild conditions withvarying functional group tolerance (Scheme 9). The cascade processinvolves copper-catalyzed aerobic oxidation of indole, hydrolysis ofamide, the copper-catalyzed decarboxylative coupling, intramo-lecularly nucleophilic addition, and oxidative aromatization. Underthe optimized reaction conditions, various indoles bearing either anelectron-donating or electron-withdrawing group on its 5th posi-tion, worked well for this reaction and afforded corresponding

Scheme 8.

tryptanthrin derivatives in moderate to good yields. Moreover, theisatins 43 with good substitution diversity were also found to bethe efficient coupling partners.

Deng and co-workers [48] introduced a simple, efficient andnovel approach for the synthesis of 2,3-diarylquinazolinones 47 viaa hydrogen-transfer strategy fromnitrobenzamides 45 and alcohols46 using iron catalysis (Scheme 10). With the optimal reactionconditions in hand (dppf, chlorobenzene, 160 �C, 24 h, argon), thereaction scope clearly demonstrated the influence of variousbenzylic alcohols on the reaction. Substituent effects on the aro-matic rings A and B of the amide were also examined. Substratesbearing electron-donating substituents on aromatic ring B could besuccessfully coupled with benzyl alcohol and afforded the productsin moderate yields.

Chiba and co-workers [49] described an unprecedented oxida-tive skeletal rearrangement of 5-aryl-4,5-dihydro-1,2,4-oxadiazoles 48 into quinazolinones 49 induced by molecular oxy-gen (Scheme 11). The reaction is likely proceeds via transient iminylradical species. The present strategy offers an atom- and step-economical alternative to existing synthetic methods but also al-lows facile construction of quinazolinone core under tin-free aer-obic radical conditions. The same strategy was further extended tothe construction of Ispinesib 57 [49c], an inhibitor of kinesinspindle protein (KSP) (Scheme 12).

Ji et al. [50] developed an efficient, facile and one-pot methodfor the synthesis of polycyclic heterocycles benzo [4,5]imidazo[1,2-c]pyrrolo[1,2-a]quinazolinones 60 from two simple and readilyavailable startingmaterials, substituted 2-(1H-benzo[d]imidazol-2-yl)anilines 58with 4-pentynoic acid 59 via an Au(I)/Ag(I)-catalyzeddomino coupling/cyclization reaction (Scheme 13). Under optimalconditions, substrate scope was examined with various sub-stituents for this cascade transformation in good to excellent yields.

Another interesting, efficient and novel method for the con-struction of 5-arylindazolo[3,2-b]quinazolin-7(5H)-one derivatives63 from 2-amino-N0-arylbenzohydrazide 61 and o-halogenatedbenzaldehyde 62 in the presence of Cu-catalysis in basic conditions

Scheme 9.

Scheme 10.

Scheme 11.


was developed by Wang and co-workers [51] (Scheme 14). Thisprocedure contains an Ullmann-type reaction and provides anefficient method to construct fused tetracyclic heterocycles.Furthermore, the protocol includes the advantages of readilyavailable reactant, inexpensive catalyst and high yields obtained fortetracyclic framework.

A new and very convenient procedure to access 3-aryl-4-imino-3,4-dihydroquinazoline-2-carbonitriles 66 from 2-amino-N0-aryl-benzamidines 64 with 4,5-dichloro-1,2,3-dithiazolium chloride 65(Appel salt) in the presence of Hünig’s base was developed byKoutentis and co-workers [52]. The target compounds were ob-tained in one-step process in moderate to good yields. The reactionprovides a convenient route to C-2 cyano substituted quinazolin-4(3H)-imines (Scheme 15).

Gou et al. [53] introduced a practical and efficient synthesis ofpyrazolo[1,5-c]quinazolines 68 and 5,6-dihydropyrazolo[1,5-c]qui-nazolines 69, including several spiro compounds, through copper-catalyzed tandem reaction of 5-(2-bromoaryl)-1H-pyrazoles 67

with carbonyl compounds and aqueous ammonia under air(Scheme 16). With the optimized reaction conditions in hand, thescope and generality of this copper-catalyzed tandem reactionleading to pyrazolo[1,5-c]quinazolines was also studied. A diversevariety of substituents including aryl-, heteroaryl-, alkenyl-, andalkyl-substituted aldehydes were all compatible with the reactionconditions to provide desired products.

Another important and straightforward iron-catalyzed diver-gent oxidative tandem synthesis of dihydroquinazolines 71 fromN-alkylanilines 70 using a TEMPO oxoammonium salt as a mild andnon-toxic oxidant was demonstrated byMancheño and co-workers[54] (Scheme 17). This approach allows for the direct homo-condensation of simple N-alkylanilines or their reaction with avariety of monosubstituted and 1,2-disubstituted olefins togenerate valuable N-containing heterocycles in one synthetic step.A variety of electron-donating and electron-withdrawing sub-stituents on anilines were tolerated leading to the desired dihy-droquinazolines in moderate yields.

Venkateswarlu and co-workers [55] attempted the reaction ofimidoformates with methyl anthranilate in presence of acetic acidfor the formation of 8H-quinazolino[4,3-b]quinazolin-8-ones forthe first time (Scheme 18). This reaction opens the possibility ofnew synthetic routes to various heterocyclic compounds. Subse-quently, the reaction has been utilized as a facile, three-component,one-pot synthesis of 8H-quinazolino[4,3-b]quinazolin-8-ones 74starting from readily available 2-aminobenzonitriles 72, triethylorthoformate, and anthranilic acids/esters/amides 73.

Paul and co-workers [56] investigated the synthesis of a series ofnovel regioisomeric hybrids of quinazoline/benzimidazole (3-allyl-2-methyl-3H-benzimidazol-5-yl)-(2-substituted-quinazolin-4-yl)-amine 87 and (1-allyl-2-methyl-1H-benzimidazol-5-yl) (2-substituted-quinazolin-4-yl)-amine 88 from readily available o-phenylenediamine and anthranilic acid (Scheme 19).

Scheme 12.

Scheme 13.

Scheme 14.


Scheme 15.

Scheme 16.

Scheme 17.


Wu and co-workers [57] produced a novel series of 6-aryl-benzo[h] [1,2,4]-triazolo[5,1-b]quinazoline-7,8-dione derivatives 92 bythree-component coupling of aldehyde 89, 2-hydroxy-1,4-naphthoquinone 90 and 3-amino-1,2,4-triazole 91 using a cata-lytic amount of sulfamic acid under solvent free conditions in good

Scheme

yields (Scheme 20). The products were obtained in high regiose-lectivity. Under the optimized conditions, a library of quinazolin-dione derivatives was afforded using aldehydes either bearingelectron-withdrawing groups (such as halide, nitro) or electron-donating groups (such as alkyl group). This method is simple andconvenient to prepare a wide range of ortho-quinone derivatives ina single-step operation.

Dong and co-workers [58] designed and synthesized a series ofazaspirocycle or azetidine substituted 4-anilinoquinazoline de-rivatives (Scheme 21). The 3-hydroxy-4-methoxy benzaldehyde 93was alkylated with 1-bromo-3-chloro propane or 1-bromo-2-chloroethane to afford the corresponding chlorides 94 or 95,respectively, whichwas then converted tomethyl benzoate 96 or 97through oxidation followed by esterification. Compound 98 or 99obtained by nitration of 96 or 97 was reduced with iron powder inacetic acid to give 100 or 101 in satisfactory yield. Cyclization of 100or 101 with formamidine acetate generated hydroxyl quinazoline

18.

Scheme 19.


102 or 103 efficiently. Chlorination with phosphorus oxychlorideproduces 104 or 105, followed by nucleophilic substitution with 3-chloro-4-fluoroaniline affords the key precursor 106 or 107. Thetarget products 108 and 109 were then obtained by halogen ex-change and then simple alkylation with various four-memberedheterocylces.

Dukat and co-workers [59] reported quinazoline 112 via a two-step reaction as previously reported [59b], using the generalmethod of Grosso et al. [59c]. Condensation of 4-chloroisatoic an-hydride 110 with S-methylisothiourea provided the given quina-zolinone intermediate 111 that was reduced with diborane to thecorresponding quinazoline (Scheme 22).

Yang and co-workers [60] reported a series of 5,6,7-trimethoxy-N-phenyl(ethyl)-4-aminoquinazoline compounds by microwaveirradiation and conventional heating methods (Scheme 23). 2,3,4-Trimethoxybenzoic acid 113 was nitrated with 70% nitric acid toproduce 114, which on esterificationwith methanol in the presenceof 98% sulfuric acid gave 115. Compound 115 was hydrogenatedwith Pd/C as a catalyst in EtOH to afford 116, which on cyclizationwith formamide yielded 117. Compound 117 was chlorinated withphosphorus oxychloride to give the key intermediate 4-choloro-

Scheme

5,6,7-trimethoxyquinazoline 118. The target compounds, 5,6,7-trimethoxyl-N-aryl-4-aminequinazoline 119 were obtained by thesubstitution reaction of 4-chloro-5,6,7-trimethoxyquinazoline 118with amine.

Abadi and co-workers [61] reported a series of 6-acrylamide-4-substituted quinazoline derivatives 124 by refluxing differentamines with formimidate 121, obtained from 2-amino-5-nitrobenzonitrile 120 with triethyl orthoformate in the presenceof catalytic amount of acetic anhydride (Scheme 24). This novelmodification is cost-effective since the quinazoline nucleus issynthesized from the formimidate derivative which is preparedfrom the much cheaper triethyl orthoformate instead of the usualN,N-dimethylformimidamide derivative prepared from the moreexpensive DMFedimethyl acetal [61b]. Furthermore, reduction ofthe nitroquinazoline derivatives 122 was done by refluxing withSnCl2 in methanol to yield the aminoquinazoline derivatives 123,which then reacted with acryloyl chloride in acetone or DMF at 0 �Cin the presence of NaHCO3 to yield the acrylamide derivatives 124.

Mizuno and co-workers [62] successfully deployed a simplemonomeric tungstate, TBA2[WO4] as an efficient homogeneouscatalyst for chemical fixation of CO2 with 2-aminobenzonitriles 125

20.

Scheme 21.


to quinazoline-2,4(1H,3H)-diones 126 (Scheme 25). A wide varietyof structurally diverse 2-aminobenzonitriles could be convertedinto the corresponding quinazoline-2,4(1H,3H)-diones in highyields at atmospheric pressure of CO2. Kinetic studies and DFTcalculations showed that TBA2[WO4] plays an important role in thisprocess.

Li et al. [63] developed a series of new 2-azolyl-3,4-dihydroquinazolines 132 by direct cyclization of imidazole or1,2,4-triazole with carbodiimides 130, which were obtained fromaza-Wittig reaction of iminophosphorane 129 with isocyanate(Scheme 26). It is noteworthy that the reaction proceeds undermildconditions to afford final products in good yields.

Prashanth and Revanasiddappa [64] described a procedure forthe synthesis of a series of novel glutamine linked 2,3-disubstitutedquinazolinone conjugates 138 from methyl anthranilate anddifferent substituted acids 133 and acid chlorides 134 (Scheme 27).The target compounds 138 were obtained in good yields.

Han and co-workers [65] discovered experimentally that qui-nazoline-2,4(1H,3H)-dione 139 can be synthesized efficiently from

Scheme

CO2 and 2-aminobenzonitrile 125 in water without any catalyst,while the reaction does not occur in organic solvents (Scheme 28).In water, CO2 can also react with different substituted 2-aminobenzonitriles to form the corresponding quinazoline-2,4(1H,3H)-diones with satisfactory yields in the absence of acatalyst. Furthermore, it was believed that this clean and simpleroute to synthesize quinazoline-2,4(1H,3H)-diones has great po-tential for industrial application.

Ali and co-workers [66]were able to report an efficient synthesisof a new series of quinazolinone derivatives 145 (Scheme 29). Syn-thesis of 2-phenyl-benzo[d] [1,3]oxazin-4-one 140was obtained bythe condensation of anthranilic acid 125 and benzoyl chloride in thepresence of pyridine. Compound 140 was refluxed with hydrazinehydrate in ethanol to afford intermediate 141. Further, the inter-mediate 141 was dehydrated with catalytic amount of GAA inethanol to yield 3-amino-2-phenyl-1H-quinazolin-4-one 142. Next,compound142was treatedwith 3-hydroxy benzaldehyde and smallamountofGAA in ethanol to afford schiff base derivative143. Finally,synthesis of 3-[(3-substitutedbenylidene)-amino]-2-phenyl-3H-

22.

Scheme 23.


quinazolin-4-one derivatives 144 was carried out by reacting 143with various alkyl halide in the presence of anhydrous K2CO3 inDMF.

Arya and co-workers [67] reported an efficient and facile syn-thesis of fluorinated benzothiazolo[2,3-b]quinazoline-2H-ones an-alogues 148 via one-pot reaction of 2-amino-6-chlorobenzothiazole145, fluorinated aldehydes 146 and dimedone 147 usingmicrowaveirradiation in the presence of ionic liquid (Scheme 30). The one-pot

Scheme

three component reactionwent smoothly in an ionic liquid (1-butyl-3-methylimidazolium hexafluorophosphate), and gave the corre-sponding fluorinated benzothiazolo[2,3-b]quinazoline derivativesin excellent yields.

Mohammadi and co-workers [68] described a successful strat-egy, efficient and convenient green synthesis for the preparation of2-aryl-3-(phenylamino)-2,3-dihydroquinazolin-4(1H)ones 151 viacyclocondensation reaction of aldehydes and 2-amino-N-

24.

Scheme 25.


phenylbenzohydrazine 150 using an inexpensive, non-toxic andeasily available Alum as a catalyst in ethanol under reflux (Scheme31).

Rambabu et al. [69] designed and synthesized a novel series ofN-indolylmethyl substituted spiroindoline-3,20-quinazolines 156by the reaction of 1-(prop-2-ynyl)-1’H-spiro[indoline-3,20-quina-zoline]-2,40(30H)-dione 154with 2-iodoanilides 155 in the presenceof 10% Pd/C, CuI, PPh3 Et3N in EtOH at 70 �C (Scheme 32). The keystarting material, that is, the terminal alkyne 154 was prepared byreacting 2-aminobenzamide 152with 1-(prop-2-ynyl)indoline-2,3-dione 153 under ultrasound irradiation at room temperature.Having established reaction conditions in hand, a variety of 2-iodoanilides with either electron-donating or electron-withdrawing substituents proceeded well to afford the targetcompounds.

El-Mekabaty and co-workers [70] successfully performed a se-ries of reactions to achieve several functionalized quinazolinonederivatives 158e171 by the reaction of 4-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl-4-methylbenzenesulfonate 157 withsome primary aromatic amines, e.g., aniline, p-chloro aniline, p-methoxy aniline, p-amino benzoic acid and p-amino acetophenone(Scheme 33). Some heterocyclic amines, such as 2-aminothiazole,2-aminobenzothiazole, 5-amino-4-phenylazo-2,4-dihydropyrazol-3-one and 3-amino-2-methylquinazolinone and diamines; like o-phenylenediamine, p-phenylenediamine, ethylenediamine, semi-carbazide hydrochloride and thiosemicarbazide were also found tobe competent partners under different reaction conditions(Schemes 34 and 35).

Hussein [71] introduced a new strategy for the synthesis of 2,3-dihydro-2-(3,4-dihydroxyphenyl) pyrazolo[5,1-b]quinazolin-9(1H)-

Scheme

one 174 by the cyclocondensation of methyl 2-((E)-3-(3,4-dihydroxyphenyl)acrylamido)benzoate 173 with hydrazine hydrate(Scheme 36). Compound 173 in turnwas synthesized by reacting theamino group of methyl anthranilate 172 with caffeic acid in thepresence of PCl3.

Darehkordi and co-workers [72] developed a novel and efficientprotocol for the synthesis of thiazolo[2,3-b]quinazoline derivatives179 under conventional magnetic stirring as well as ultrasonicirradiation (Scheme 37). Treatment of cyclohexanone 175 with ar-omatic aldehyde 176 and thiourea 177 in the presence of modifiedmontmorinollite nanostructure or HCl as a catalyst under heatingand solvent-free conditions produced 8-benzylidene-4-aryl-3,4,5,6,7,8-hexahydroquinazoline-2(1H)-thione 178 which wasutilized as a key intermediate for the synthesis of new thiazolo[2,3-b]quinazoline derivatives via the reaction with diethyl acetylenedicarboxylate. Ultrasonic irradiation displayed dramaticallyreduced reaction times compared to conventional magnetic stirringmethod and also provided the desired products in high yields andpurity.

Wang and co-workers [73] reported an iodine-catalyzed syn-thesis of 1,5-dioxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazo-line-3a-carboxylic acid derivatives 182 from the reaction of 2-aminobenzamide 180 and 2-oxopentanedioic acid 181 in ionicliquids (Scheme 38). Under optimized reaction conditions, bothelectron-donating and electron-withdrawing groups on 2-aminobenzamide core were tolerated successfully affordingquinazoline-carboxylic acid derivatives in high yields.

Safaei et al. [74] described a highly efficient and environmentalbenign procedure for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones 184 via the condensation of carbonyl compounds 183with 2-aminobenzamide 152 using a glycerol based ionic liquidwith a boron core as a new and reusable promoting medium(Scheme 39). This method avoids the use of hazardous catalysts orsolvents. This methodology also founds good generality, impressiveyield, short reaction time, cleaner reaction profile, ease of productisolation, simplicity, potential for recycling of the reaction medium,and finally agreement with the green chemistry protocols. Thisprocedure has also been applied successfully for the synthesis ofsome novel bis(pyrazolinone) derivatives.

Bergman and co-workers [75] described the synthesis of 2-(2-aminophenyl)-2,4-diphenyl-1,2-dihydroquinazoline 186 by the re-action of anthranilonitrile 125 with phenylmagnesium bromide

26.

Scheme 27.

Scheme 28.


which yielded a dianion 185 which on heating at 140 �C gave finalproduct (Scheme 40).

Chen and co-workers [76] reported an impressive one-potprocedure for the synthesis of azoquinazolinones 189 fromsubstituted 2-halobenzamides 187 and different N-heterocycles188 via Cu(I)-catalyzed CeN coupling/CeH activation/CeN forma-tion process under O2 (Scheme 41). A number of azoquinazolinones

Scheme

containing different azole rings and substituents were obtained ingood yields. Under the reaction scope, N-aryl group of 2-iodo-benzamides, the N-aryl substrate with electron-donating groups(CH3, OCH3) gave lower yield of product than the others withelectron-withdrawing groups (Cl, NO2).

Yang and Chen [77] discovered a process for the preparation of aseries of quinazoline derivatives 191 in good to excellent yields byexposing 1,2-dihydroquinazoline 3-oxides 190 to visible light inacetonitrile without the presence of any external sensitizers(Scheme 42).

Wang and co-workers [78] reported an efficient iodine-catalyzed reaction of 2-aminobenzamides 152 with 1,3-cyclohexanediones 147 providing access to quinazolinone de-rivatives 192 (Scheme 43). The variation in reaction temperature isa key factor to get different diversified products. Controlling thereaction temperature at 110 �C yielded the unexpected bis-quinazolinone derivatives 193.

Moghimi and co-workers [79] developed new and efficient ap-proaches for the synthesis of a series of 4(3H)- and 4,40(3H,3H0)-quinazolinone derivatives 195, 196 and 2-(5-alkyl-1,2,4-oxadiazol-

29.

Scheme 30.

Scheme 31.


3-yl)quinazolin-4(3H)-one 197 in good yields, via the reactions ofdiaminoglyoxime 194 and anthranilic acid derivatives or methyl 2-aminobenzoate and acetic anhydride in acetic acid as the solventunder reflux conditions (Scheme 44).

Wang and co-workers [80] established an efficient protocol togenerate indolo[1,2-c]quinazolines 199 from acyclic alkyne sub-strates 198 by ZnBr2-promoted domino hydroaminationecycliza-tion strategy (Scheme 45). The dichotomous properties of zinc saltsinvolving alkynophilicity and oxophilicity assured a one-pot for-mation of five- and six-membered nitrogen-containing rings in theskeleton.

Shingare and co-workers [81] developed an efficient syn-thetic route for 2,3-dihydroquinazolin-4(1H)-ones 200 using 2-morpholinoethanesulfonic acid as a potential and new organo-catalyst (Scheme 46). The described synthetic protocol repre-sents a novel and very simple route for the preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives. In addition, micro-wave irradiation technique is successfully implemented for car-rying out the reactions in shorter reaction times.

Scheme

Grundt and co-workers [82] successfully showed that thetryptanthrin compounds 202 can be synthesized by Oxone inducedoxidation of indole-3-carbaldehyde 201 and its 5-halogensubstituted analogues (Scheme 47).

Raval and co-workers [83] developed an efficient and simpleone-pot method for the synthesis of isoindolo[2,1-a]quinazolines205 using Saccharomyces cerevisiae (baker’s yeast) as a whole cellbiocatalyst at room temperature (Scheme 48). This methodologymay prove useful for other transformations also which has pro-duced the targeted moiety in good to moderate yield at roomtemperature under ultrasonic irradiation.

Desroses and co-workers [84] reported a convenient and effi-cient T3P�-assisted protocol for the synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives 207 (Scheme 49). Thismethod has several advantages including a practical simplicity, ashort reaction time (10e15 min), the use of very mild conditions(room temperature) and an easy access (isolation) to the com-pounds in good to excellent yields. This process was applicable todiverse substrates, aliphatic and aromatic aldehydes with electron-

32.

Scheme 33.

Scheme 34.


Scheme 35.

Scheme 36.

Scheme 37.

Scheme 38.

Scheme 39.


Scheme 40.

Scheme 41.

Scheme 42.


donating or -withdrawing substituents reacted very well, affordinggood to excellent yields of 2,3-dihydroquinazolinones. The natureor the position of the substituent had negligible influence on therate of the reaction.

Chiba and co-workers [85] reported an orthogonal aerobicconversion of N-benzyl amidoximes 208 to quinazolinones 209(Scheme 50). The reaction tolerates both electron-rich and -defi-cient benzene rings as well as indolyl and pyridyl motifs as sub-stituents R1, providing quinazolinones in moderate yields.Introduction of a methoxy group as substituent did not retard thereaction, affording 7-methoxylquinazolinone in 58% yield.

Chen et al. [86] disclosed the first convenient and practicalexample of a copper-catalyzed cascade reaction of (2-aminophenyl)methanols 210 with aldehydes 206 using the combination ofcerium nitrate hexahydrate and ammonium chloride leading to a

Scheme

wide range of 2-substituted quinazolines 211 in moderate toexcellent yields (Scheme 51). The efficiency of this transformationwas demonstrated by compatibility with a wide range of functionalgroups including electron-donating as well as electron-withdrawing. Generally, (2-aminophenyl)methanols possessingan electron-poor substituent on the phenyl group provided aslightly higher yield of cyclization product. Steric effects of sub-stituents had also an obvious impact on the yield of the reaction.

Rostami and co-workers [87] reported an elegant and eco-friendly method for the preparation of 2-substituted-2,3-dihydroquinazolin-4(1H)-ones 213 from direct cyclocondensationof anthranilamide 152 with aldehydes and ketones 212 using N-propylsulfamic acid supported onto magnetic Fe3O4 nanoparticles(MNPs-PSA) as a recoverable and recyclable nanocatalyst (Scheme52). The products were obtained in good to excellent yields inwater at 70 �C. The characteristic advantages of this catalyst arerapid, simple and efficient separation by using an appropriateexternal magnet, which minimizes the loss of catalyst during sep-aration, and reusable without significant loss of activity.

Kidwai and Chauhan [88] demonstrated a convenient synthesisof a series of [1,2,4]triazolo[5,1-b]quinazolinones 215 by conden-sation of 3-amino-1,2,4-triazole 91, aldehydes 206 and 1,3-dicarbonyl compounds 214 using Nafion-H� as an effective andenvironmental friendly heterogeneous catalyst in polyethyleneglycol as solvent (Scheme 53). The catalyst exhibited excellentrecyclability without any significant loss of catalytic activity. Thisprotocol offers several advantages like simple experimental pro-cedure and work-up, mild conditions, higher yields and recycla-bility of the catalyst as well as solvent.

43.

Scheme 44.

Scheme 45.


Jiang et al. [89] unveiled an enantioselective synthesis of bio-logically important spiro[indoline-3,2-quinazoline] scaffolds 217with a quaternary stereogenic center via an isatin-involved asym-metric catalytic tandem condensation/amide addition with 2-aminobenzamides 152 (Scheme 54). The reaction provided fair toexcellent enantioselectivities (up to 95% ee) of spiro compoundswith a wide range of substituents present on both phenyl rings.

Mansoor and co-workers [90] described an efficient, simple,green and environmentally benign methodology for the synthesisof 2,3-dihydro-2-phenylquinazolin-4(1H)-ones 218 using catalyticamounts of succinimide-N-sulfonic acid via the cyclocondensationof 2-aminobenzamide 152 with various aldehydes 206 (Scheme55). A series of aldehydes with either electron-rich or electron-poor groups attached to aromatic ring were investigated. Thesubstitution groups on the aromatic ring had no obvious effect on

Scheme 46.

the reaction yield. This method offers several advantages such ashigh yields, simple procedure, low cost, short reaction times, mildreaction conditions, and use of a recyclable catalyst.

Besson and co-workers [91] developed a microwave-assistedone-pot procedure for the synthesis of 3-(prop-2-ynyl)quinazo-lin-4(3H)-ones 219 in high yields (Scheme 56). Various substituentshave been tolerated to afford the desired products.

Santra et al. [92] developed an environmentally benign nanoCuO catalyzed “on-water” strategy for one-pot synthesis of iso-indolo[2,1-a]quinazolines 221 by a three-component coupling ofisatoic anhydride 149, 2-carboxybenzaldehyde 220 and amines 204in high yields (Scheme 57). Under the optimized reaction condi-tions, several aryl, heteroaryl and alkyl amines reacted efficientlyaffording title compounds. Water plays a major role to acceleratethis transformation through hydrogen bond mediated ‘electro-phileenucleophile dual activation’. The catalyst can be reusedseveral times without significant loss of catalytic activity.

Gharib and co-workers [93] reported an efficient one-pot three-component synthesis of 2,3-dihydroquinazolin-4(1H)-ones 222 bythe condensation of isatoic anhydride 149with primary amines 204or ammonium carbonate and aromatic aldehydes 206 under refluxconditions in water in the presence of catalytic amounts of silica-supported preyssler nanoparticles (SPNP) (Scheme 58). This strat-egy was also extended to the synthesis of bis-dihydroquinazolinones 224 by a novel pseudo-five-componentcondensation of isatoic anhydride 149, a primary amine 204, anda dialdehyde 223 in water. This method is found to possess severaladvantages including the recyclability of catalyst without loss ofcatalytic activity.

Batra and Dighe [94] reported an efficient iodine-mediated elec-trophilic tandem cyclization of substituted 2-alkynylbenzaldehydes225 with 2-aminobenzamides 152 to furnish isoquinoline-fusedquinazolinones 226 (Scheme 59). A variety of substituents including

Scheme 47.

Scheme 48.

NH2

O

NH2

T3P (50% in EtOAc)

NH

NH

R

R = Ph, i-Pr, t-Bu, 2-Cl-Ph, 3-Cl-Ph, 4-Cl-Ph, 3-OMe-Ph, 4-OMe-Ph,2-CN-Ph, 4-CF3-Ph, o-tolyl, p-tolyl, 4-NO2-Ph, thiazolyl, naphthyl

O

HR

152 206 207

MeCN

OPOPOP

O OO

O

CH3

H3C

H3C

T3P

85-94%

Scheme 49.

Scheme 50.


electron-rich and electron-poor moieties were found to be suitablefor this transformation. The presence of the iodo group confers anadvantage for further derivatization via robust cross coupling re-actions, which has been exemplified via Sonogashira and Suzukicross-couplings.

Boulcina and co-workers [95] demonstrated a simple and effi-cient protocol for the synthesis of 1,2-dihydroquinazolines 229

Scheme

catalyzed by 4-(N,N-dimethylamino)pyridine (DMAP) from readilyavailable aromatic or heteroaromatic aldehydes 206, 2-aminobenzophenone 227, and ammonium acetate 228 undermild conditions (Scheme 60). Under the optimized reaction con-ditions, the scope and generality of reaction was investigated. Theelectronic nature of the substituents on the benzene ring had nosignificant influence on the reactivity. An unsubstituted phenylgroup or aryl groups with electron-donating substituents affordedhigh yields, as did those with electron-withdrawing groups. How-ever, the presence of 2-chloro-, 4-N,N-dimethylamino- or 4-hydroxy-groups on the aromatic ring gave products with slightlydiminished yields.

Rahman et al. [96] synthesized several benzoquinazolin-2-one/thione derivatives 231 by using a catalytic amount of task specificionic liquid, [1-methyl-3-(4-sulfobutyl)imidazolium-4-methylbenzenesulfonate] through a one-pot multicomponentBiginelli reaction of a-tetralone 229, aldehyde 206 and urea/thio-urea 230, 177 in excellent yields within a short reaction time(Scheme 61). To explore the generality and scope, several struc-turally diverse aldehydes were treated with a-tetralone and urea/thiourea under optimized reaction conditions and the resultsrevealed that both aromatic aldehydes substituted with electron-donating or electron-withdrawing groups underwent clean

51.

Scheme 52.

Scheme 53.

DCE, 70 °C, 5 Å MS

R = H, 5-Me, 5-ClR1 = H, 4-F, 6-F, 5-Cl, 6-Cl, 6-Br, 7-Br, 7-MeR2 = H, Me, Bn

152 216 217

5 mol% cat.

NH2

NH2

O

RNR2

O

O

R1

N

NHHN

O

O

R2

R1

R

OOP OOH

iPr

iPriPr

iPr

iPriPrcat.40-82%, 42-95% ee

Scheme 54.

H2O, 70 °C

R = H, 3-F, 4-F, 3-Br, 4-Br, 3-NO2, 4-Me, 4-OMe, 4-Cl, 3-OH, 4-OH, 4-NMe2

152 206 218

5 mol% cat.

NH2

NH2

O

cat.

CHOR

NH

NH

O

RN

O

O

SO3H

86-95%

Scheme 55.

AcOH, 100 °C, MW, 15 min 219

DMFDMADMF, 100 °C, MW, 15 minCO2H

NH2 N

N

O

H2N

82 one-pot

ON

ODMFDMA

90%

Scheme 56.


Scheme 57.

Scheme 58.

Scheme 59.


conversion to the desired products. The catalyst was also foundcompatible with various functional groups such as eBr, eNO2. Thisprotocol has the advantages of operational simplicity, reusability ofthe catalyst, no need of column chromatographic separation, andshorter reaction time.

Wang et al. [97] reported the synthesis of 2,3-dihydroquinazolin-4(1H)-ones 232 by the cyclocondensation re-action of anthranilamide 152 with aldehydes 206 under ultrasonicirradiation using a poly(4-vinylpyridine) supported acidic ionicliquid as a catalyst (Scheme 62). The products were obtained in

good to excellent yields. In addition, the catalyst could be easilyrecovered by the filtration and reused six times without significantloss of catalytic activity. More importantly, the use of ultrasonicirradiation can obviously accelerate the reaction.

Wu and co-workers [98] developed an interesting zinc-catalyzed oxidative methodology for the construction of quinazo-linone frameworks 233, 234 from readily available 2-aminobenzamide 152, with benzyl alcohols 46 (Scheme 63). Thetarget products were obtained with a range of diverse substitutionsin good to excellent yields. On the other hand, aldehydes 206 were

Scheme 61.

Scheme 62.

Scheme 63.

Scheme 60.


Scheme 64.


applied as coupling substrates instead of benzyl alcohols usingwater as the reaction medium and products were isolated in goodyields.

Saha and Panja [99] described an atom-efficient, atom-eco-nomic, eco-friendly, solvent-free, high yielding, multicomponentgreen strategy to synthesize highly functionalized quinazoline de-rivatives 235 through one-pot reaction of 2-aminobenzophenone227, aromatic aldehyde 206, and ammonium acetate 228 by usingmagnetic IL, butylmethylimidazolium tetrachloroferrate (bmim[FeCl4]) as a catalyst (Scheme 64). The suitability of this method fora variety of aromatic aldehydes was also investigated which clearlyshowed that substitution of the aldehyde did not appreciably affectthe yield of the desired product. However, the presence of a nitrogroup at C-5 position of 2-aminobenzophenone affects the reactiontime significantly.

Fu and co-workers [100] developed a general and efficientcopper-catalyzed aerobic oxidative method for the synthesis of N-fused heterocycles including H-indolo[1,2-c]quinazolines 240,

Scheme

benzo[4,5]imidazo[1,2-c]quinazolines 241, and pyrazolo[1,5-c]qui-nazolines 242 by using readily available a-amino acids 239 as thenitrogen source (Scheme 65). The reactions underwent N-arylation,aerobic oxidative dehydrogenation, intramolecular cyclization anddissociation of formic acid. This method should provide a generaland practical strategy for the construction of N-fused heterocycles.

Wei and co-workers [101] were able to achieve an iodine cata-lyzed one-pot two-step oxidative system for cyclization of primaryalcohols 46 with o-aminobenzamides 152 to quinazolinones 243using DMSO as the oxidant (Scheme 66). The products were ob-tained in good to excellent yields via in situ oxidation of primaryalcohols to aldehydes. The procedure is suitable for aromatic oralkyl primary alcohols.

3. Pharmacological applications

Quinazolines and quinazolinones are among the most usefulheterocyclic compounds from both synthetic and medicinal

65.

Scheme 66.


chemistry aspects. The structural design of these scaffolds hasattracted a great deal of attention because of their ready accessi-bility, diverse chemical reactivity, and broad spectra of biologicalactivities. Although, the literature is enriched with numerous ex-amples of these motifs exhibiting potential biological activities, wehave highlighted here the most recent (2013) developments in theactivity profile of these compounds.

3.1. Anticancer activity

Yan et al. [46] developed a simple and efficient procedure for thepreparation of a polyhalo 2-aryl-4-aminoquinazoline library. Thenewly synthesized library of compounds was evaluated for in vitrogrowth inhibitory activity against a series of human cells accordingto a previous method [102]. Cisplatin (DDP) was used as thereference drug. The assay results revealed that some of the com-pounds including 244e247 showed good activity against the tumorcells. Among them, 244 was the most active compound, morepotent than cisplatin against SKOV-3, U2-OS, A549, and MCF-7 cells. Moreover, 244 is up to 40 times more active than cisplatinagainst MCF-7 cells. The structureeactivity relationship of thetarget compounds indicated that all polyhalo-substituted de-rivatives showed in vitro growth inhibitory activity. All in all, 5,7,8-trifluoro substituted quinazolines (trifluoroquinazolines) had bet-ter activity to A549 and MCF-7 tumor cell lines than the 5,7-difluoro-8-chloro substituted quinazolines (difluoro-quinazolines)and 5,7,8-trichloro substituted quinazolines (trichloroquinazo-lines). This makes the compound 244 one of the most promisingleads for future, further pending structural modifications based onthe valuable information obtained.

Mohareb and co-workers [103] reported several novel thiazole,pyrimidine and benzylidene derivatives derived from quinazolinescaffold. The synthesized compounds were subjected to the NCI’sin vitro, one dose primary anticancer assay, using a 3-cell line panelconsisting of MCF-7 (breast), NCI-H460 (lung), and SF-268 (CNS)cancers. With regard to sensitivity against individual cell lines,compound 248 showed considerable activity against MCF-7, NCI-H460 and SF-268 with GI50 concentrations of 0.4, 0.1, and 0.9 mM,respectively. Compound 249 showed the highest potency againstMCF-7 at a concentration of 0.01 mM, and is thus almost two-foldsmore active than the positive control doxorubicin. Compound 250also showed a remarkable activity against all three cell lines withGI50 concentrations of 0.03, 0.02, and 0.05 mM, respectively. Struc-tureeactivity correlation of the synthesized compounds revealedthat the substitution of unsubstituted benzylidenes into the 3rdposition of the quinazoline pharmacophore greatly enhances thecytotoxicity of the compound.

Yang and co-workers [60] reported a new series of 5,6,7-trimethoxy-N-phenyl(ethyl)-4-aminoquinazoline compounds,

prepared by microwave irradiation and conventional heatingmethods. The synthesized compounds were screened for theiranticancer activities. Some of the title compounds were found toinhibit EGF-induced ERK1/2 phosphorylation in PC3 cells effec-tively, which indicated that the position of trimethoxy groups onthe phenyl ring affected the antiphosphorylation activities of 4-phenyl(ethyl)quinazoline compounds. Preliminary structureeac-tivity relationship analysis showed that the 4-phenyl ring con-taining a fluorine atom or trifluoromethyl group generally had goodantiphosphorylation activities. Further investigation showed thatsome compounds showed strong inhibition activities against ERK1/2 phosphorylation induced by EGF at 1.28 mM. Interestingly, 4-substituted phenylethylamino-5,6,7-trimethoxyquinazoline com-pounds also possessed strong antiphosphorylation activities, suchas 251. MTT assay showed that some of the compounds had mod-erate to strong anticancer activities. The inhibition rate of 251against PC3, BGC823, and PC3 cells at 10 mM were 90.6 � 9.1,88.2� 6.1, and 90.4� 2.8%, respectively. Also, the IC50 values of 251were 6.2� 0.9, 3.2� 0.1, and 3.1�0.1 mM against PC3, BGC823, andBcap37 cells, respectively, which were much higher than those ofPD153035 (8.3 � 1.1, 14.4 � 1.5, and 15.7 � 1.2 mM, respectively).Acridine orange/ethidium bromide staining, Hoechst 33258 stain-ing, DNA ladder, and flow cytometry analyses revealed that 251induced cell apoptosis in PC3 cells, with apoptosis ratios of 11.6% at1 mM and 31.8% at 10 mM after 72 h.

Qi and co-workers [104] designed and synthesized a series ofthirteen novel quinazoline nitrogen mustard derivatives and evalu-ated for their anticancer activities in vitro and in vivo. Cytotoxicityassays were carried out in five cancer cell lines (HepG2, SH-SY5Y,DU145, MCF-7 and A549) and one normal human cell line (GES-1).The clinical drugs, Sorafenib and Gefitinib were used as positivecontrol. Among the screened compounds, 252 showed very low IC50toHepG2 (the IC50 value is 3.06mM),whichwas lower thanSorafenib.Compound252 could inhibit cell cycle at S andG/Mphase and inducecell apoptosis. In the HepG2 xenograft model, 252 exhibited signifi-cant cancer growth inhibition with low host toxicity in vivo.

Ahmed and Youns [105] described the synthesis of three novelseries of 6,8-dibromo-4(3H)quinazolinone derivatives. Some of thesynthesized quinazolinone derivatives were tested for their anti-tumor activity against the human breast carcinoma cell line MCF-7.Most of the tested compounds have shown promising anticanceractivities against the human breast cancer cell line MCF-7,compared to doxorubicin (positive control) at very low concen-trations. Among them, compound 253 was found to be the mostactive with IC50 value of 1.7 mg/mL. It is interesting to note that aminor alteration in the molecular configuration of the investigatedcompounds may have a pronounced effect on anticancer activity.

Hour et al. [106] reported a series of 2-aryl-6-substituted qui-nazolinones and assayed for cytotoxicity in vitro against five human


tumor cell lines, including M21 (malignant melanoma), CH27 (lungsquamous carcinoma), H460 (non-small cell lung cancer), Hep3B(hepatoma) and HSC-3 (oral cancers). Some of the tested com-pounds showed strong cytotoxic effects against the five testedcancer cell lines, with IC50 values ranging from 0.033 to 8.74 mM,while the remaining compounds were found to be inactive(IC50 > 10 mM). SAR studies indicated that compounds bearing 2-(naphthalen-1-yl) groups exhibited strong cytotoxic activityregardless of which one of the five functional groups substituted attheir position 6. As for compounds bearing 2-(1H-indol-3-yl)groups, only those substituted with 6-(pyrrolidin-1-yl) or 6-(piperidin-1-yl) were active; however, their activity decreasedsignificantly. All the compounds bearing 2-(benzo[b]thiophen-3-yl)groups were inactive in spite of which functional groupssubstituted at their 6-positions. Overall, 254 bearing both 2-(naphthalen-1-yl) and 6-(pyrrolidin-1-yl) moieties showed thehighest activity, with IC50 values of 0.03, 0.05, 0.08, 1.35 and0.04 mM against M21, CH27, H460, Hep3B and HSC-3 cells respec-tively. Compound 255 bearing both 2-(naphthalen-1-yl) and 6-methoxyl moieties showed slightly decreased activity, with IC50values of 0.09, 0.09, 0.07,1.94 and 0.15 mMagainst M21, CH27, H460,Hep3B and HSC-3 cells respectively. From the above findings,compounds 254 and 255 appear to be more potent anti-proliferative agents and may be used in future to develop potentanticancer drugs.

Sharma and Ravani [107] reported an efficient synthesis of novelquinazolinone derivatives from the reaction of N-benzoylsubstituted piperazine-1-carbothioamide with 2-chloromethylquinazolinone derivatives and screened for their in vitro cytotoxicactivity by MTT assay. The cell lines used were NCI (human lungcancer cell), MCF 7 (Breast cancer cell), and HEK 293 (Normalepidermal kidney cell). Result of screening on cell line showedmoderate to good anticancer activity for all the compounds. Amongthe tested samples, compound 256 (IC50¼ 1.1�0.03 mM)was foundto be the most active compared to standard methotrexate(IC50 ¼ 2.20 � 0.18 mM) and 5-florouracil (IC50 ¼ 2.30 � 0.49 mM).Structureeactivity relationship of synthesized analogues suggestedthat the presence of NH linker with aryl moiety at the third positionof quinazolinone ring was important for potent anticancer activity.Electron-rich group on phenyl ring at the third position of quina-zolinone ring gave better anticancer activity than unsubstitutedphenyl and electron-poor group. Activity by substituted piperazineat 2nd position of thiazole linked with quinazolinone scaffold gavebetter activity in the order of H > CH3 > COeC6H5. These findingsmay impart new direction to medicinal as well as bio-chemists forfurther investigations of quinazolinone-thiazole containing anti-cancer agents.

Pathania et al. [108] designed and synthesized novel quinazo-linedione derivatives for the treatment of pancreatic cancer. Theassay results led to the discovery of a potent analogue, 257 (6-[(3-acetylphenyl)amino]quinazoline-5,8-dione) that displayed anti-proliferative activities in low micromolar range in both drug-sensitive and drug-resistant cancer cells. Treatment with 257 cau-ses Akt activation resulting in increased cellular oxygen con-sumption and oxidative stress in pancreatic cancer cells. Moreover,oxidative stress induced by 257 promoted activation of stress ki-nases (p38/JNK) resulting in cancer cell death. Treatment with anti-oxidants was able to reduce cell death confirming ROS-mediatedcytotoxicity.

Kovalenko and co-workers [109] synthesized a series of novelN-aryl(alkaryl)-2-[(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-6-yl)thio]acetamides and screened for their anticancer activity.Twenty nine of the synthesized compounds were tested, and mostof them displayed anti-tumor activities against leukaemia, mela-noma, lung, colon, CNS, ovarian, renal, prostate and breast cancers

cell lines. Screening of anticancer activity in vitro yielded the mostactive compounds 258e262 in micromolar concentrations with theGI50 level (logGI50 is from�7.57 to�4.05 for different cell lines, andlogGI50 mean graph midpoint varied from �5.30 to �4.50). More-over, compound 259 had a distinctive selectivity against renalcancer, 260dcolon cancer and melanoma and 261drenal cancer.The highest sensitivity to compound 259 showed renal cancer celllines A498 (logGI50 ¼ �7.57).

Al-Salahi and co-workers [110] synthesized a series of twentyfive 2-methylsulfanyl-[1,2,4]triazolo[1,5-a]quinazoline derivativesand investigated their cytotoxic effects against various humancancer cell lines (Hep-G2, MCF-7, HCT-116, and HeLa cells). Theresults analysis revealed that none of the tested compounds werecytotoxic to both MCF-7 and HeLa cells, as concluded from theirhigh IC50 values (>50 mg/mL). On the other hand, the treatment ofHep-G2 cells with selected compounds led to some cytotoxicity(IC50 < 50), with compounds 263 and 264 showing the highestcytotoxic effect and the lower IC50 values (9.34 and 19.22 mg/mL).Similarly, same compounds exhibited cytotoxicity with (IC50 < 50)in the treatment of HCT-116 cells, where compounds 263 and 264showed the highest cytotoxic effects with the lower IC50 values of11.51 and 17.39 mg/mL, respectively. Although 263 and 264 showedthe highest cytotoxic effect against Hep-G2 and HCT-116 cells,attributed to the presence of fused ring in 263 and 5-ethoxy moietyin 264, which seemed to be essential for the antitumor activityagainst HCT-116 and Hep-G2, theywere less effective as anti-canceragents than the known drug paclitaxel.

Cao et al. [111] reported a novel series of 4-substituted-pipera-zine-1-carbodithioate derivatives of 2,4-diaminoquinazoline andtested for their antiproliferative activities against five human can-cer cell lines including A549 (lung cancer), MCF-7 (breast adeno-carcinoma), HeLa (cervical carcinoma), HT29 and HCT-116(colorectal cancer). Most of the synthesized compounds showedbroad spectrum antiproliferative activity (IC50 ¼ 1.47e11.83 mM), ofwhich 265e267 were the most active members with IC50 values inthe range of 1.58e2.27, 1.84e3.27 and 1.47e4.68 mM against fivecancer cell lines examined, respectively. To search for more efficientanticancer agents and to investigate the structureeactivity rela-tionship of 4-substituted-piperazine-1-carbodithioate derivativesof 2,4-diaminoquinazoline, methyl, cyclohexyl, benzyl, phenyl, aswell as pyridin-2-yl and pyrimidin-2-yl groups were selected toserve as “R” substituents in the target compounds. Particularly, anumber of substituted phenyl groups were incorporated toexamine the electronic or steric effects of substituents attached tothe phenyl ring on the antiproliferative activity. These resultsindicate that an aryl group connected to the N4 position of piper-azine ring is more favorable for antiproliferative activity than analkyl, cycloalkyl, arylalkyl or heteroaryl group. Furthermore,different from 5-FU, compounds 265e267 induced DNA damage inHCT-116 cells leading to the G2/M checkpoint activation and G2/Marrest.

Kamal et al. [112] synthesized a series of novel quinozolinolinked 4b-amidopodophyllotoxin conjugates and evaluated fortheir anticancer activity against human pancreatic carcinoma(Panc-1) as well as breast cancer cell lines such as MCF-7 and MDA-MB231 by employing MTT assay. Several compounds such as 268e271 were found to be more cytotoxic than the other compounds inthis series. The flow cytometry analysis also showed that thesecompounds caused significant G2/M cell-cycle arrest in MCF-7 cells. Treatment of MCF-7 cells with effective compounds for 24 hat 4 mM concentration lead to increase in expression of p53 andcyclin B1 proteinwith concomitant decrease in Cdk1. Further, theseeffective conjugates have exhibited inhibitory action on integrin(aVbIII). Furthermore, the MCF-7 cells that were arrested and lostthe proliferative capacity undergo mitochondrial mediated


apoptosis by activation of caspases-9. Thus, these conjugates havethe potential to control breast cancer cell growth by effecting tumorangiogenesis and invasion.

Park and co-workers [113] identified several potent PARP-1 in-hibitors with submicromolar IC50 values (77e79 nM) throughpharmacophore-based virtual screening of Korean Chemical Data-base. Theyhave also examined the chemosensitizationof cisplatin bypre-treatment of PARP-1 inhibitors in cisplatin-resistant humangastric cancer cells. The two most potent PARP-1 inhibitors, 272 and273, effectively improved the sensitivity of cisplatin-resistant humangastric cancer cells to cisplatin by inhibiting PARP-1 catalytic activity.

Noolvi and Patel [114] synthesized a novel series of 3-(substituted benzylideneamino)-7-chloro-2-phenyl quinazoline-4(3H)-ones and tested for their anticancer activity. Among thetested compounds, 7-chloro-3-{[(4-chlorophenyl) methylidene]amino}-2-phenylquinazolin-4(3H)-one 274, with GI50 valueof �5.59 M, TGI value of �5.12 M, and LC50 value of �4.40 Mshowed remarkable activity against CNS SNB-75 cancer cell line.

Russu and Xu [115] designed and synthesized a series of com-pounds based on a quinazoline scaffold pharmacophore modelwhich may have high binding affinity with the p50 subunit of NF-kB. The compound series with phenyl substitution at the 2-positionof the quinazoline proved to be more effective at inhibiting NF-kBfunction both theoretically and experimentally. These compoundsalso reduce the proliferation of numerous tumor cell lines and themean GI50 for compound 275 is 2.88 mMagainst the NCI-60 cell line.At the same time, compound 275 can induce significant apoptosisin EKVX cell line at the concentration of 1 mM.

Barraja and co-workers [116] successfully prepared a series ofpyrrolo[3,4-h]quinazolines by annelation of the pyrimidine ring onthe isoindole moiety. A diverse variety of substituents has beentolerated in the current synthetic strategy which gave impressiveresults. Some of the newly synthesized derivatives showed aninteresting cytotoxicity in many tumor cell lines and were activeeven in a multi-drug resistant cell line. The most cytotoxic de-rivatives 276e280 induced cell death mainly by apoptosis, asdemonstrated by the onset of the apoptotic peak in cell cycleanalysis and by the classical AnnexinV/PI test.

Yang and co-workers [117] synthesized three series of noveltryptanthrin derivatives and the structureeactivity analysis wasundertaken. The optimization led to the identification of 281, whichexhibited the inhibitory activity at a nanomolar level. In vitro 281dramatically augmented the proliferation of T cells. When admin-istered to Lewis lung cancer (LLC) tumor-bearing mice, 281 signif-icantly inhibited IDO-1 activity and suppressed tumor growth. Inaddition, 281 reduced the numbers of Foxp3þ regulatory T cells(Tregs), which are known to prevent the development of efficientantitumor immune responses.

Wiese and co-workers [118] synthesized and investigated a se-ries of differently substituted quinazoline compounds. A diverserange of variations at positions 2, 4, 6 and 7 of the quinazolinescaffold were carried out to develop a structureeactivity-relation-ship analysis for these compounds. From the results, it was foundthat compounds bearing a phenyl substituent at position 2 of the 4-anilinoquinazoline scaffold weremost potent. On the aniline ring atposition 4 of the quinazoline moiety substituents like NO2 and CNled to very high BCRP inhibition potencies. Compound 282, ananilinoquinazoline bearing a phenyl ring at position 2 and meta-nitro substitution on the 4-anilino ring, was found to have thehighest therapeutic ratio (Figs. 7 and 8).

3.2. Anti-tumor activity

Paul and co-workers [56] reported a series of novel regioiso-meric hybrids of quinazoline/benzimidazole viz. (3-allyl-2-methyl-

3H-benzimidazol-5-yl)-(2-substituted-quinazolin-4-yl)-amine and(1-allyl-2-methyl-1H-benzimidazol-5-yl) (2-substituted-quinazo-lin-4-yl)-amine derivatives. The newly synthesized compoundswere screened for in vitro antitumor activities against 60 tumor celllines panel assay which includes nine tumor subpanels namely;leukemia, non-small cell lung, colon, CNS, melanoma, ovarian,renal, prostate and breast cancer cells. Preliminary in vitro anti-tumor screening revealed that only compounds 283 and 284showed significant growth inhibition (more than 60%) for most ofthe cancer cell lines. On the basis of activity results, it has beenproved that (3-allyl-2-methyl-3H-benzimidazol-5-yl)-(2-amino-quinazolin-4-yl)-amine derivatives are more active antitumoragents than their regioisomeric analogues (1-allyl-2-methyl-1H-benzimidazol-5-yl)-(2-aminoquinazolin-4-yl)-amine. Overall,compound 284 showed broad spectrum antitumor activityshowing effectiveness toward numerous cell lines belonging todifferent tumor subpanels. Thus, the introduction of pyrrolidinemoiety is preferred over chloro and other secondary amines at 2-position of quinazoline. Molecular docking was also performedfor 284 which reinforced the activity results by showing probablemode of action of this compound for anticancer activities.

Wu and co-workers [57] demonstrated a regioselective syn-thesis of 6-aryl-benzo[h][1,2,4]-triazolo[5,1-b]quinazoline-7,8-diones. All the synthesized compounds were evaluated for theirantiproliferative activities against the human gastric carcinoma cellline SCG7901, hepatoma cell line HepG2. It is clearly observed thatall the tested compounds showed moderate to good anti-proliferative activities against the tested cancer cell lines. Amongthem, the compounds 285e288 showed better antitumor activityagainst all cancer cell line.

Chilin and co-workers [119] reported some novel anilinoqui-nazoline derivatives carrying modifications in the quinazolinescaffold and in the aniline moiety. The synthesized compoundswere subjected to antitumor evaluation. Taken together, activityresults indicated that the functionalization of the aniline moietywith a further benzene ring together with deoxygenated ringsfused to quinazoline core lead to compounds 289e291 character-ized by high antiproliferative activity through the inhibition of awide panel of both receptor and nonreceptor TKs.

El-Azab and co-workers [120] synthesized novel series of 2-(substituted thio)-3-phenethylquinazolin-4(3H)-one and 2-([5-mercapto-4-(substituted)-4H-1,2,4-triazol-3-yl)methylthio]-3-phenethylquinazolin-4(3H)-one derivatives. The newly synthe-sized compounds were subjected to the National Cancer Institute(NCI) in vitro disease-oriented human cells screening panel assayfor in vitro antitumor activity. The results of this study demon-strated that compound 292 showed sensible selective activitiestoward colon cancer cell lines (HCT-116 and HCT-15), melanomacancer cell lines (MDA-MB-435), renal cancer cell lines (AHCN, RXF393, and UO-31), prostate cancer cell line (PC-3), and breast cancercell lines (MCF7, MDAMB-231/ATCC, T-47D, and MDA-MB-468).Compound 293 also yielded reasonable selective activities towardleukemia cell line (HL-60(TB), MOLT-4, and CCRFCEM), non-smallcell lung cancer cell lines (NCI-H226, NCI-H460, and NCI-H522),and colon cancer cell line (HCT-116). In addition, non-small celllung cancer cell line (EKVX), colon cancer cell line (HT29), renalcancer cell line (UO-31), and breast cancer cell lines (MCF7,MDAMB-231/ATCC, and T-47D) showed moderate sensitivity tocompound 294.

Ji and co-workers [121] designed and synthesized three series ofnovel 4-benzothiazole amino quinazolines Dasatinib derivatives.The entire target compounds were investigated for their in vitrocytotoxic activity by the MTT-based assay against 6 human cancercell lines. Structureeactivity relationship observed with thedifferent quinazoline moieties modification at the C-2 amine of the

Fig. 7. Structures of potential anticancer agents.

Fig. 8. Structures of potential anticancer agents (continued).



benzothiazole nucleus. Almost all the 2,4,6-trimethylaniline seriescompounds demonstrated potent anti-proliferation effects withIC50 values less than Dasatinib in 6 cell lines. Among them, themostsignificant inhibition was achieved for compound 295.

El-Subbagh and co-workers [122] designed and synthesized anew series of 2-heteroarylthio-6-substituted-quinazolin-4-one an-alogues and evaluated for their antitumor activity against severaltumor cell lines. A single dose (10 mM) of the test compounds wereused in the full NCI 60 cell lines panel assay which includes ninetumor subpanels namely; leukemia, non-small cell lung, colon, CNS,melanoma, ovarian, renal, prostate, and breast cancer cells. Onlycompound 296 showed broad spectrum potency toward severaltumor cell lines with GI50 values range of 25.8e41.2%.

Liu and co-workers [123] synthesized a series of quinazoline-2,4(1H,3H)-dione analogues and screened in vitro antitumor ac-tivity using the NCI antitumor screening program. Among thetested compounds, several derivatives showed significant anti-tumor potential. Four compounds, for which the average logGI50values were below �6 including compounds 297 (logGI50 ¼ �6.1),298 (logGI50 ¼ �6.13), 299 (logGI50 ¼ �6.44), and 300(logGI50 ¼ �6.39), significantly inhibited the in vitro growth of 60human tumor cells.

El-Azab and co-workers [124] designed and synthesized a novelseries of 2-(3-phenethyl-4(3H)quinazolin-2-ylthio)-N-substitutedanilide and substituted phenyl 2-(3-phenethyl-4(3H) quinazolin-2-ylthio)acetate and evaluated for their in vitro antitumor activity.Among the tested compounds, 301 possessed remarkable broad-spectrum antitumor activity which almost sevenfold more activethan the known drug 5-FU with GI50 values of 3.16 and 22.60 mM,respectively. Compound 301 also exhibited remarkable growthinhibitory activity pattern against renal cancer (GI50 ¼ 1.77 mM),colon cancer (GI50 ¼ 2.02 mM), non-small cell lung cancer(GI50 ¼ 2.04 mM), breast cancer (GI50 ¼ 2.77 mM), ovarian cancer(GI50 ¼ 2.55 mM) and melanoma cancer (GI50 ¼ 3.30 mM). Dockingstudy was also performed for compound 301 into ATP binding siteof EGFR-TK which showed similar binding mode to erlotinib.

Georgey and co-workers [125] described the synthesis ofdifferent series of 6-iodo-2-phenoxymethyl 3-substituted quinazo-lin-4(3H)-ones derivatives and tested for their in vitro antitumoractivity againstMCF-7 breast cell line. Among the tested compounds,302 exhibited a remarkable antitumor activity (IC50¼ 5.49 mmol/mL)almost similar to that expressed by the reference drug, Doxorubicin(IC50 ¼ 5.46 mmol/mL) (Fig. 9).

3.3. Anti-hepatitis activity

Chen and co-workers [126] identified several indole-basedquinazoline derivatives with anti-hepatitis activity. SAR studies ofthe indole substituents were performed to optimize potency andPK properties. The initial good potency of the primary amide groupat the indole nitrogen substituent led to the eventual discovery ofthe novel quinazolinone series of highly potent inhibitors. Opti-mization of C4, C5, and C6 substituents led to the identification of4,5-furanylindole as the best core. The C2 carboxylic acidsdemonstrated better PK than corresponding acylsulfonamides. Af-ter all, compound 303 was identified as the lead with very goodpotency and rat oral PK AUC.

Botyanszki and co-workers [127] discovered small moleculeType III Phosphatidylinositol 4-Kinase Alpha (PI4KIIIa) inhibitors asanti-hepatitis C (HCV) agents. They have also described the syn-thesis and structure�activity relationships associated with thebiological inhibition of PI4KIIIa and HCV replication. These effortsled directly to identification of quinazolinone 304 that displayshigh selectivity for PI4KIIIa and potently inhibits HCV replicationin vitro (Fig. 10).

3.4. Antidepressant activity

Dukat and co-workers [59] identified 2-amino-6-chloro-3,4-dihydroquinazoline HCl 305 a novel 5-HT3 receptor antagonistwith antidepressant-like action in the mouse tail suspension test(TST). Empirically, 305 was demonstrated to be a 5-HT3 receptorantagonist (two-electrode voltage clamp recordings using frogoocytes; IC50 ¼ 0.26 mM), and one that should readily penetrate thebloodebrain barrier (log P ¼ 1.86). 5-HT3 receptor antagonistsrepresent a potential approach to the development of new anti-depressants, and 305 is an example of a structurally novel 5-HT3receptor antagonist that is active in a preclinical antidepressantmodel (i.e., the mouse TST) [128] (Fig. 11).

3.5. Antileishmanial agents

Chauhan and co-workers [129] prepared four novel series ofquinazolinone hybrids bearing interesting bioactive scaffolds (py-rimidine, triazine, tetrazole, and peptide). Most of the synthesizedanalogues exhibited potent leishmanicidal activity against intra-cellular amastigotes (IC50 from 0.65 � 0.2 to 7.76 � 2.1 mM) ascompared tomiltefosine (IC50¼ 8.4� 2.1 mM) and non-toxic towardthe J-774A.1 cell line and Vero cells. The SAR analysis revealed thatamong the synthesized quinazolinone hybrids, quinazolino-ne�pyrimidine, triazine, and ferrocene containing quinazolino-ne�peptide displayed potent antileishmanial activity. Compounds306 and 307 exhibited significant in vivo inhibition of parasite73.15 � 12.69 and 80.93 � 10.50% against Leishmania donovani/hamster model. These results indicated that the active compoundsrepresent a new structural lead for this serious and neglecteddisease.

Mohareb and co-workers [103] reported several novel thiazole,pyrimidine and benzylidene derivatives derived from quinazolinescaffold. The antileishmanial activity of the newly synthesizedproducts was tested on L. donovani amastigotes. The assay resultsindicated that among the synthesized quinazoline derivativesanalyzed, phenyl thiourea derivative 308, thiazole derivative 309,and indole derivative 310 displayed the most significant activityagainst L. donovani amastigotes growing in macrophages similar tothat seen with axenic amastigotes at 50 mM with an average inhi-bition of 98, 96, and 92%, respectively. SAR analysis revealed thatthe addition of a bulky phenyl group to the thiazole ring in deriv-ative 309 resulted in a remarkable increase in the average inhibi-tion (Fig. 12).

3.6. Anticonvulsant activity

Ali and co-workers [66] synthesized a new series of 2-phenyl-3-(3-(substituted-benzylideneamino))-quinazolin-4(3H)-one de-rivatives. The synthesized quinazolinone derivatives were screenedfor their anticonvulsant activity against standard models MES(maximal electroshock seizure test) for their ability to reduceseizure spread. Motor impairment screening was also carried outby rotorod test method. The data obtained for screened compoundsrepresents that compounds 311 and 312 having R ¼ ethyl and n-propyl groups, respectively, were found to be the most active of theseries showing activity both at 0.5 and 4.0 h at lower doses of 100and 30 mg/kg, respectively. On the basis of these findings, it can beconcluded that the activity may be attributed to the presence ofadequate long and straight aliphatic chain i.e., ethyl and propyl thatprovide adequate lipophilicity and well fitted to receptor site.

Quan and co-workers [130] described the syntheses and anti-convulsant activity evaluation of 5-phenyl[1,2,4]triazolo[4,3-c]quinazolin-3-amine derivatives. Their anticonvulsant activity andneurotoxicity were evaluated by the maximal electroshock seizure

Fig. 9. Structures of anti-tumor agents.


test (MES) and the rotarod test, respectively. The majority of thecompounds prepared were effective in the MES screens at a doselevel of 100 mg/kg. Among these compounds, the most promisingwas compound 313, which showed an ED50 value of 27.4 mg/kg anda protective index (PI) value of 5.8. These values were superior tothose provided by valproate (ED50 and PI values of 272 and 1.6,respectively) in the MES test in mice.

Fig. 10. Potential anti-HCV agents.

Alagarsamy and Saravanan [131] designed and synthesized alibrary of quinazolin-4(3H)-one derived pyrazole analogues andtested for their antiepileptic activity byMES and scPTZ model alongwith its neurotoxicity. The structure of the title compounds satis-fied all the pharmacophoric structural requirements that is, thepresence of quinazolin-4(3H)-one moiety as hydrophobic portion,N as electron donor system, the presence of carbonyl group andanother hydrophobic distal aryl ring responsible for controlling thepharmacokinetic properties of the antiepileptic. In this series,generally compounds possessing 2-methyl quinazolinone ringexhibited significant antiepileptic activity in comparison to 2-phenyl quinazolinone ring. Among the screened compounds,

Fig. 11. Compound with antidepressant character.

Fig. 12. Structures of compounds with antileishmanial activity.


some derivatives exhibited significant activity in MES screening,while others showed significant antiepileptic activity in scPTZmodel. These active compounds were selected for oral adminis-tration in rats at 30 mg/kg dose. Among those, compounds 314exhibited excellent antiepileptic activity in oral dose than standarddrug phenytoin.

El-Subbagh and co-workers [132] designed and synthesized anew series of quinazoline analogues and evaluated for their anti-convulsant activity. Several compounds showed70e100%protectionagainst PTZ-induced seizures acting as GABAA receptor agonists.Among them, compound N-(3,4,5,6-tetrachlorophthalimido)-2-[(3-phenyl-4-oxo-6-methyl-3H-quinazolin2-yl)-thio]acetamide, 315showed moderate activity whereas compound 2-[6-iodo-4-oxo-2-(thiophen-2-yl)-quinazolin-3(4H)-yl]-isoindoline-1,3-dione 316exhibited remarkable anticonvulsant potential with ED50 values of457 and 251 mg/kg; TD50 values of 562 and 447 mg/kg; PI values of1.22 and 1.78, LD50 values of 1288 and 1380 mg/kg, and TI values of2.82 and 5.50, respectively. From the data analyzed, compound 316proved to be almost twofold more active than the standard drugsodium valproate.

Khan and Malik [133] reported a new synthesis of quinazolin-4(3H)-one substituted 1H and 2H-tetrazole derivatives and evalu-ated for anticonvulsant screening based on the NIH anticonvulsantdrug development (ADD) program protocol. From the biologicalactivity of the probed compounds, it was observed that from theinventory of 25 examined compounds, 317e319 proved to be ofclinical significance. The quinazolinone nuclei dissembled as themainstay for the persuading the anticonvulsant activity. Theintroduction of the benzyloxy tetrazole moiety as the core fragmentsynergized the activity. The presence of the free carbonyl and sul-phonyl group attributed to the amplification of the anticonvulsantstimulus. Moreover, it is clear that good anticonvulsant activity wasconfined to compounds containing free oxygen functionality.

Zayed and co-workers [134] synthesized some novel derivativesof 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones andevaluated for their anticonvulsant activity by the maximalelectroshock-induced seizure and subcutaneous pentylenete-trazole tests. The neurotoxicity was assessed using rotorod test. Allthe tested compounds showed considerable anticonvulsant activityin at least one of the anticonvulsant tests. Compounds 320e322proved to be the most potent compounds of this series with

relatively low neurotoxicity and low toxicity in the median lethaldose test when compared with the reference drugs. From the datashown above, it is clear that the presence of electron-withdrawinggroup at aromatic ring enhanced the activity when compared tounsubstituted or electron-donating group in the phenyl ring.

Revanasiddappa and co-workers [135] synthesized a novel classof N-substituted glycosmicine derivatives and examined for theiranticonvulsant activity by maximal electroshock induced seizures(MESs) test and their neurotoxic effects were determined byrotorod test in mice. Among the synthesized compounds, 323e326exhibited an optimal anticonvulsant efficacy with no neurologicaltoxicity (Fig. 13).

3.7. Anti-inflammatory activity

Hussein [71] reported a synthesis of 2,3-dihydro-2-(3,4-dihydroxyphenyl) pyrazolo[5,1-b]quinazolin-9(1H)-one and testedfor their anti-inflammatory activity by using the method of Winteret al. and diclofenac sodium was used as a reference standard. Thetested compound 327 showed promising anti-inflammatory activ-ity compared with the reference drug.

Eweas and co-workers [136] designed and synthesized somenovel 2-pyridyl (3H)-quinazolin-4-one derivatives and evaluatedfor their anti-inflammatory activity. All the tested compoundsshowed good anti-inflammatory activity in comparison to thereference standard indomethacin. Among them, compounds 328and 329 showed the highest anti-inflammatory activity.

Saravanan and co-workers [137] synthesized a new series ofnovel quinazolin-4(3H)-one derivatives and tested for their anti-inflammatory activity. In general, halogen substituted compoundsparticularly trifluoromethyl analogue exhibited potent anti-in-flammatory activity. Among all tested compounds trifluoromethylanalogue 330 exhibited better activity which is more potent thandiclofenac. A deep fall in activity was observed when tri-fluoromethyl group was replaced with methoxy or nitro or hy-droxyl group.

Abbas and co-workers [138] reported some of new 3-(4-chlorophenyl or 4-fluorophenyl)-6-iodo-4-oxo-3,4-dihydroquinazo-line derivatives carrying Schiff bases and various heterocyclic motifssuch as oxazolone, imidazolidine, pyrazolidine, pyridine, and pyrimi-dine. The synthesized compounds were screened for their anti-

Fig. 13. Compounds with anticonvulsant activity.


inflammatory activity. The screening of the anti-inflammatory activity(chronic model) of the tested 4(3H)-quinazlinone compoundsrevealed that, the 3-(4-fluorophenyl)-2-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylimino)-methyl]-6-iodo-3H-qui-nazolin-4-one 331, which has azomethine side chain at C-2 positionendingwith a pyrazolemoiety and chlorophenyl at position 3, showedstrong anti-inflammatory activity. Other compounds like 332 and 333incorporating pyrazole and pyrazoline moieties at C-2 also showedstrong anti-inflammatory activity. On the other hand, compounds334e336 which possess hydrazone, thiazole, and oxazole at C-2 po-sition, respectively, also exhibited strong anti-inflammatory activities,ranged from 0.8 to 0.9 potencies comparable to the reference drug.

Al-Salahi and co-workers [110] synthesized a series of twentyfive 2-methylsulfanyl-[1,2,4]triazolo[1,5-a]quinazoline derivativesand investigated their anti-inflammatory activity. The tested sam-ples exhibited different extents of anti-inflammatory activity,ranging from strong to weak activity. Some compounds haveshown potential significant anti-inflammatory effects compared tothat of dexamethasone and the control, which ranged from 75 to86% inhibition compared to LPS-induced cells, whereas someothers were found to possess moderate effects, with an inhibitionrange of 50e70% with respect to LPS induced cells. Overall, these

findings revealed that compounds 337e341 are promising multi-potent anti-inflammatory agents.

Zayed and Hassan [139] synthesized some novel 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones bearing sulfonamidederivatives and evaluated for their anti-inflammatory activity bycarrageenan-induced hind paw edema test using ibuprofen as astandard drug. Among the screened compounds, 342 and 343 withaliphatic side chain were more active than that with aromatic one.Compound 343, was found to be the most active compound withrelative potency of 74% of the reference’s potency (Fig. 14).

3.8. Antimicrobial activity

Prashanth and Revanasiddappa [64] reported a new series ofnovel glutamine linked 2,3-disubstituted quinazolinone conjugatesfrom methyl anthranilate and different substituted acids and acidchlorides. The newly prepared compounds were obtained in goodyields. All compounds were screened for their antibacterial activityagainst Gram-positive (Bacillus subtilis and Staphylococcus aureus)and Gram-negative bacteria (Pseudomonas aeruginosa and Escher-ichia coli) and for antifungal activity against Candida albicans andAspergillus flavus using paper disk diffusion technique. The

Fig. 14. Compounds with anti-inflammatory activity.


minimum inhibitory concentrations of the compounds were alsodetermined by agar streak dilution method. Compound 344 wasfound to exhibit the most potent in vitro anti-microbial activityamong the screened series of compounds. A close analysis of thescreening results and structures of active compounds revealed thatthe halogen substitution of phenyl ring increased antimicrobialactivity. It is interesting to note that the electron-withdrawingproperty of the phenyl ring is important, which is corroboratedby the eminent activity of compounds with halogen group anddecreased activity of compounds with either methyl or methoxygroup in the phenyl ring. Hence, the replacement of methyl ormethoxy group in place of halogens shows decrease in antibacterialactivity.

El-Mekabaty and co-workers [70] synthesized a variety of novelquinazolinone derivatives containing various heterocyclic motifs.Several of the newly synthesized target compounds were evaluatedfor their in vitroantibacterial activityagainstGram-positive S. aureus(ATCC 25923) and Streptococcus pyogenes (ATCC 19615) bacteria andGram-negative Penicillium phaseolicola (GSPB 2828) andP. fluorescens (S 97) bacteria. They were also evaluated for theirin vitro antifungal potential against Fusarium oxysporum andAspergillus fumigatus fungal strains. Chloramphenicol, cephalothinand cycloheximide were used as reference drugs. The resultsrevealed that most of the tested compounds displayed variableinhibitory effects on the growth of the tested Gram-positive andGram-negative bacterial strains and also against antifungal strains.

In general, most of the tested compounds revealed better activityagainst the Gram-positive rather than the Gram-negative bacteria.Regarding the structureeactivity relationship of the thiazole, ben-zothiazole and pyrazole against Gram-positive bacteria, the resultsrevealed that compounds 345e349 exhibited broad spectrumantibacterial profile against the tested organisms. Compounds 347e349were equipotent to chloramphenicol in inhibiting the growth ofS. aureus (MIC 3.125 mg/mL), while its activity was 50% lower thanthat of chloramphenicol against S. pyogenes. Compounds 345 and346 showed 50% of the activity of chloramphenicol (MIC 6.25 mg/mL), but they were equipotent to cephalothin in inhibiting thegrowth of S. aureus and S. pyogenes (MIC 6.25 mg/mL).

Mohammadi and co-workers [68] described a reaction leadingto an efficient synthesis of novel 2-aryl-3-(phenylamino)-2,3-dihydroquinazolin-4(1H)-one derivatives and screened for theiranti-bacterial activity against several Gram-positive and Gram-negative bacteria. Tetracycline and gentamicin were used as stan-dards. The screening results indicated that some of the testedcompounds exhibit significant antibacterial activities whencompared with the reference drugs. It was observed that thecompound containing N(Me)2 substituted group in 4-position of 2-aryl-3-(phenylamino)-2,3-dihydroquinazolin-4(1H)-one 350shows better activity than the other test compounds and thereference, tetracycline and gentamicin, drugs.

Menon and co-workers [140] synthesized a series of novelcationic fullerene derivatives bearing a substituted-quinazolin-


4(3H)-one moiety as a side arm were synthesized using the 1,3-dipolar cycloaddition reaction and screened antimicrobial activityagainst selected Gram-positive (S. aureus and S. pyogenes) andGram-negative (P. aeruginosa, K. pneumonia and E. coli) bacterialand fungal strains (C. albicans, Aspergillus clavatus, and Aspergillusniger). Amongst the activities of screened derivatives, it is veryobvious that the molecule havingmore lipophilic substitution, suchas 351, has better activity than the other compounds for Gram-negative bacteria.

Al-Amiery and co-workers [141] synthesized a series of func-tionalized quinazolinone derivatives and the antibacterial activitywas also evaluated against various pathogenic Gram-positive andGram-negative bacterial strains. The antibacterial screening datashowed that the synthesized compounds 352 and 353 exhibitantibacterial properties. The significant activity of the synthesizedcompounds 352 and 353 can be explained by the electron delo-calization over the whole molecules. This delocalization increasesthe lipophilic character of these molecules and favors theirpermeation through the lipoid layer of bacterial membranes. Theincreased lipophilic character of these molecules seems to beresponsible for their enhanced antibacterial activities. The in vitroantifungal effects of the investigated compounds 352 and 353against two fungal spices (A. niger and C. albicans) were tested.Compound 352 was found to exhibit antifungal activity against allthe fungi used in this study. Fluconazole was used as the referencecompound for fungi. Compound 353 displayed potential antifungalactivity against C. albicans.

Shi et al. [142] described a novel strategy for the construction ofpolyhalobenzonitrile quinazolin-4(3H)-one derivatives. All of thenewly prepared compounds were screened for antimicrobial ac-tivities against four strains of bacteria (Gram-positive bacterial:S. aureus and B. cereus; Gram-negative bacteria: E. coli andP. aeruginosa) and one strain of fungi (C. albicans). Among thesynthesized compounds, 5-(dimethylamino)-8-(2,4,5-trichloro-isophthalonitrile) quinazolin-4(3H)-one 354 exhibited significantactivity toward Gram-positive, Gram-negative bacterial, and thefungal strains. The MIC (0.8e3.3 mg/mL) and MBC (2.6e7.8 mg/mL)for this compound were close to those of nofloxacin, chlorothalonil,and fluconazole, making it the most potent antimicrobial agents inthe series.

Song and co-workers [143] synthesized twenty-seven novel (E)-3-[2-arylideneaminoethyl]-2-[4-(trifluoromethoxy)anilino]-4(3H)-quinazolinone derivatives. The synthesized compounds werefurther subjected to various assays of biological activity includingin vitro antifungal and antibacterial activities. Preliminary SARanalysis indicated that eCH3, eNO2, eOH or N,N-di-methyl groupson the benzene ring (substituted for R) enhanced the antifungaland antibacterial activity of the synthesized compounds. Moreover,introduction of eF, eCH3, eNO2, or eOH aromatic compoundsresulted in moderate to good antifungal activities against Gibberellazeae, F. oxysporum, and Sclerotinia sclerotiorum. Antibacterial testsshowed that all of the synthesized final products containing 2-furyl,eOH, or eNO2 groups exhibited significant antibacterial activityagainst Ralstonia solanacearum and Xanthomonas oryzae. In addi-tion, these assays demonstrated that the inhibition rates of com-pounds 355e357 were better than that of the commercialbactericides thiodiazole-copper and bismerthiazol.

Guillon et al. [144] synthesized a structural analogue of albaco-nazole inwhich the quinazolinone ring is fused by a thiazole moietyled to thediscoveryof anew triazolewithbroad-spectrumantifungalactivity. This new compound 358 displayed preliminary in vivoantifungal efficacy in amicemodel of systemic candidiasis. All of thebiological results are close to those observed for voriconazole oralbaconazole. This work confirmed the promising interests of a newazole compound bearing an original fused tricyclic scaffold.

Dixit and co-workers [145] designed a novel series of 4-(aminoor acetamido)-N{[3-(substituted aryl)-4-oxo-3,4-dihydroquinazolin-2-yl]methyl}benzenesulfonamide derivativesto assimilate 4-quinazolone and sulfonamide moieties in a singlemolecular framework. All these compoundswere screened for theirin vitro antimicrobial activity. The minimum inhibitory concentra-tions of the synthesized compounds against various bacteria(S. aureus, B. cereus, E. coli, K. pneumonia, P. aeruginosa) and fungi(A. niger, C. albicans) were measured by broth microdilution assay.The results of in vitro antimicrobial evaluations of the synthesizedcompounds revealed that several compounds were found topossess varied degree of antibacterial and antifungal activities.Among the compounds screened, 359 and 360 emerged with morepotent inhibitory action. The data also revealed that the presence ofvarious groups on substituted phenyl ring at N-3 as well as 4-aminobenzenesulfonamide substituent bridged at C-2 of 4-(3H)-quinazolinone ring has more influence on the antimicrobialactivity.

El-Subbagh and co-workers [122] designed and synthesized anew series of 2-heteroarylthio-6-substituted-quinazolin-4-oneanalogues and evaluated for their in vitro antimicrobial activity.Among the tested compounds, 361e365 showed a remarkablebroad-spectrum activity against both Gram-positive and Gram-negative bacteria.

Saravanan and co-workers [137] synthesized a new series ofnovel quinazolin-4(3H)-one derivatives and tested for their anti-microbial activity. All the synthesized compounds were evaluatedfor their in vitro antibacterial and antifungal activity by agar streakdilution method. The MICs of Ciprofloxacin and Ketoconazole weredetermined in parallel experiments to control the sensitivity of thetest organisms. Among the tested compounds, 366 exhibited themost significant activity withMIC value of 15.62 mg/mL. The currentresults revealed that most of the synthesized derivatives exhibitedsignificant antimicrobial activity. The potent antibacterial andantifungal activity exhibited by compound 366might be due to thepresence of electron-withdrawing substituent like trifluoromethyl.While other compounds with electron-donating substituents likemethyl, methoxy, and hydroxyl groups exhibited less in vitro anti-microbial activity.

Jauhari and co-workers [146] reported a reaction sequence forthe preparation of a series of 1-[2-(6-nitro-4-oxo-2-phenyl-4H-quinazolin-3-yl)-ethyl]3-phenyl ureas. The newly synthesized finalcompounds were assayed in vitro antimicrobial activity by usingserial broth dilution technique. Several compounds showed sig-nificant activity against different bacterial strains. Good inhibitionwas observed for compounds 367e371 against strain E. coli at40 mg/mL of MIC, among them compounds 367 and 368 showed11 mm zone of inhibition at concentration 70 mg/mL and com-pounds 369-371 showed 11 mm zone of inhibition at 40 mg/mL.From the results obtained, structureeactivity relationship studieswere carried out and effect of the substituent at the phenyl ring offinal compounds have been evaluated. For bacterial strain E. coli,compounds having electron-donating groups (CH3 and SCH3) at thephenyl or cyclohexyl ring were found to be more potent. Similarly,for antifungal activity, compound 367 was found to be the mostactive against the strain C. albicans, showing inhibition potency at10 mg/mL of MIC and 11 mm of zone of inhibition at 20 mg/mL and20 mm zone of inhibition at 300 mg/mL.

Buha et al. [147] reported novel series of 1-N-substituted-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-yl)urea/thiourea derivatives and 1-N-substituted-3-(7-(4-methylpiperazin-1-yl)-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-yl)urea/thiourea derivatives and screened for antimicrobial activityagainst S. aureus, B. subtilis, P. aeruginosa, and E. coli. Biological re-sults indicated that the synthesized compounds showed a broad


spectrum activity against both Gram-positive and Gram-negativebacteria at MIC values between 6.25 and 100 mg/mL. Compound372 showed a broad spectrum of activity andwas found to be activeagainst all tested species. It was found that presence of electron-withdrawing group on the phenyl ring of both the urea and thio-urea derivatives significantly increases the activity.

Desai et al. [148] reported a synthesis of some novel fluorinecontaining 5-arylidene derivatives bearing different pharmaco-phores and heterocyclic systems like quinazolinone along with 4-thiazolidinone. The synthesized compounds were evaluated fortheir in vitro antimicrobial activity against Gram-positive bacteria(S. aureus and S. pyogenes), Gram-negative bacteria (E. coli andP. aeruginosa) and fungi (C. albicans, A. niger and A. clavatus) usingserial broth dilution method. Several compounds possessedpotent activity but 373-379 were found to be the most note-worthy derivatives identified in the present study because oftheir remarkable in vitro antimicrobial potency. SAR indicatesthat the presence of electron-withdrawing groups like chloro,bromo, fluoro and nitro substituents on the aromatic ringincreased the activity of compounds compared to those withother substituents.

Zayed and Hassan [139] synthesized some novel 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones bearing sulfonamidederivatives and evaluated for their antibacterial activity againstGram-positive bacteria S. aureus (MTCC 96) and Staphylococcusepidermis (MTCC 435) and Gram-negative bacteria P. aeruginosa(MTCC 741) and E. coli (MTCC443) at 100 mg/mL concentration usingdimethylsulfoxide (DMSO) as a solvent. Antibacterial assay of allthe test compounds showed good activities against both of Gram-positive and Gram-negative bacteria. These activities were rangedfrom 61.91% up to 95.23% from the activity of the standard. Themost potent compounds were found to be 380 and 381 againstS. aureus.

Ji and co-workers [149] designed and synthesized a novel seriesof 1-methyl-3-substituted quinazoline-2,4-dione derivatives andevaluated for their in vitro antimicrobial activities against six strainsof bacteria and five fungi. Almost all designed compounds showedactivities against MRSA which has emerged resistance againststreptomycin, especially compounds 382-384 showed good activityagainst MRSA with the MIC values of 4 mg/mL. The antifungal ac-tivities against A. flavus of almost all the compounds were com-parable to fluconazole (Figs. 15 and 16).

3.9. Antiviral activity

Peng et al. [150] isolated 14 indole alkaloids, including six newones, from the mangrove-derived fungus Cladosporium sp. PJX-41.The antiviral activities of isolated compounds against influenza Avirus (H1N1) were evaluated by the CPE inhibition assay. Thesecompounds exhibited differing antiviral activities against influenzavirus A (H1N1). This class of alkaloids, which has unique structuralfeatures including prenylated indole derivatives, quinazoline-containing indole derivatives, and pyrazinoquinazoline-containing indole derivatives, is frequently isolated from Asper-gillus species. Among tested compounds, some exhibited notableanti-H1N1 activities (ribavirin as positive control, IC50 ¼ 87 mM)with IC50 values of 82e87 mM. The most active compounds werefound to be 385 and 386 with IC50 values of 82 mM.

Luo et al. [151] designed and synthesized a series of novel(1E,4E)-1-aryl-5-[2-(quinazolin-4-yloxy)phenyl]-1,4-pentadien-3-one derivatives and evaluated for antiviral activity. Antiviral bio-assays indicated that most of the compounds exhibited promisingex vivo antiviral bioactivities against tobacco mosaic virus (TMV)and cucumber mosaic virus (CMV) at 500 mg/mL. SAR studyrevealed that compounds 387e389 could possess appreciable

protective bioactivities on TMV ex vivo by approximately 50% (EC50)at 257.7, 320.7 and 243.3 mg/mL (Fig. 17).

3.10. Analgesic activity

Eweas and co-workers [136] designed and synthesized somenovel 2-pyridyl (3H)-quinazolin-4-one derivatives and evaluatedfor their analgesic activity. All the tested compounds showed goodanalgesic activity in comparison to the reference standard indo-methacin. Among them, compounds 390 and 391 showed thehighest analgesic activity.

Saravanan and co-workers [137] published a new series of novelquinazolin-4(3H)-one derivatives and tested for their analgesicactivity. In general, halogen substituted compounds particularlytrifluoromethyl analogue exhibited potent anti-inflammatory ac-tivity with negligible ulcer index. Among the tested compounds, 2-(2-(4-(trifluoromethyl)benzylidene)hydrazinyl)-N-(4-(2-methyl-4-oxoquinazolin-3(4H)-yl)phenyl) acetamide 330 exhibited least ul-cer index (0.55 � 0.31) which is about one-third of the ulcer indexof reference standards. Out of entire tested compounds, 2-(2-(4-methoxybenzylidene)hydrazinyl)-N-(4-(2-methyl-4-oxoquinazolin-3(4H)-yl) phenyl) acetamide 392 was found topossess highest ulcer index (0.86 � 0.53) which is about 51% of theulcer index of diclofenac and aspirin. Among all the tested com-pounds trifluoromethyl analogue 330 exhibited better activitywhich is more potent than diclofenac. A deep fall in activity wasobserved when trifluoromethyl group was replaced with methoxyor nitro or hydroxyl group.

Abbas and co-workers [138] reported some of new 3-(4-chlorophenyl or 4-fluorophenyl)-6-iodo-4-oxo-3,4-dihydroquinazo-line derivatives carrying Schiff bases and various heterocyclic motifssuch as oxazolone, imidazolidine, pyrazolidine, pyridine, and py-rimidine. The synthesized compounds were screened for their anal-gesic activity. The screening of the analgesic activity of the tested4(3H)-quinazlinone compounds revealed that, the activitywas nearlyincreased by time and all compounds showed moderate analgesicactivity compared to that of novalgin except the 3-(4-fluorophenyl)-2-[(1,5dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylimino)methyl]-6-iodo-3H-quinazolin-4-one 331 exhibited stronganalgesic activities (Fig. 18).

3.11. Antitubercular activity

Menon and co-workers [140] reported a series of novel cationicfullerene derivatives bearing a substituted-quinazolin-4(3H)-onemoiety as a side arm were synthesized using the 1,3-dipolarcycloaddition reaction of C60 with azomethine ylides generatedfrom the corresponding Schiff bases of substituted quinazolinones.In vitro evaluation of antimycobacterial activity of the synthesizedcompounds was carried out against Mycobacterium tuberculosis(H37RV). A very pronounced enhancement in the antimycobacterialactivity can be seen on attachment of the fullerene spheroid to thequinazolinone group. Among the synthesized compounds, 351 in-hibits the growth of M. tuberculosis effectively at MIC 1.562 mg/mLwith inhibition of 98.83%, which is comparable to that of theexisting front-line drug isoniazid and rifampicin which have 99%inhibition.

Kim and co-workers [152] published an efficient synthesis ofnew tryptanthrin analogues together with a systematic investiga-tion of their in vitro antitubercular activity. Electron-withdrawingsubstituents in ring A or D enhanced antitubercular activity,while introduction of a cyclic amine moiety in ring D resulted ingenerally poor antitubercular activity. For selected analogues,in vitro ADME properties were examined and their PK propertieswere evaluated in mice and rats. Compound 393 exhibited MICs of

Fig. 15. Structures of compounds with antimicrobial potential.


0.5 mg/mL (MABA) and 11.5 mg/mL (LORA) and an oral bioavailabilityof 30% in rats, the highest among the analogues evaluated. Com-pound 394 demonstrated MICs of 0.14 mg/mL (MABA) and 24.0 mg/mL (LORA) and an oral bioavailability of 8% in the rat.

Pandit and Dodiya [153] reported a new series of 2-(substituted-phenyl)-3-(((3-(pyridin-4-yl)-1-(p-tolyl)-1H-pyrazol-4-yl)methylene)amino)quinazolin-4(3H)-ones. In vitro evaluationof the antitubercular activity was carried out at the TuberculosisAcquisition Antimicrobial Coordinating Facility (TAACF) screeningprogram, Alabama, USA. The result of antitubercular activitydemonstrated that the activity is considerably affected by sub-stitutions at the phenyl ring of the pyrazoleequinazolinone nu-cleus. For the antitubercular activity, isoniazid is taken as astandard, which showed a percentage inhibition of 99 at an MIC

range of below 6.25 mg/mL. It has been observed that compounds395e397 having chloro, methyl, and methoxy group at secondposition, showed excellent antitubercular activity with percentageinhibition of 96, 94, and 93, respectively at an MIC range below6.25 mg/mL, whereas compound having chloro group at para po-sition, and compound having nitro group at meta position showedexcellent antitubercular activity with percentage inhibitions of 90and 92, respectively, at the same MIC range. Hence, there isenough scope for further study in the developing these as goodlead compounds.

Gupta and co-workers [154] established a useful strategy for thesynthesis of various substituted 5,6-dihydro-8-methoxybenzo[h]quinazolin-2-amine derivatives in good yields by an efficientmethodology. The synthesized compounds were evaluated for their

Fig. 16. Structures of compounds with antimicrobial potential (continued).

Fig. 17. Structures of antiviral agents.


in vitro anti-tubercular activity againstM. tuberculosisH37Rv strain.Among the tested samples, compounds 398 and 399 exhibitedsignificant anti-tubercular activity at MIC values 50 and 100 mMconcentrations (Fig. 19).

Fig. 18. Compounds wit

3.12. Antioxidant activity

Prashanth and Revanasiddappa [64] reported a series of novelglutamine linked 2,3-disubstituted quinazolinone conjugates and

h analgesic activity.

Fig. 19. Structures of compounds with antitubercular activity.


tested for their antioxidant activity. When tested for their antioxi-dant activity, compounds 400 and 401 showed potent radicalscavenging activity, while compound 402 had moderate effectagainst 2,2-diphenyl-1-picrylhydrazyl, hydroxyl, nitric oxide, andsuperoxide radical scavenging assays. These results suggest that thequinazolinone analogues 400 and 401 could be considered as usefultemplates for future development to obtain more potent antioxi-dant agents. The better activity of compound 401 (IC50 ¼ 14.3 mg/mL) having hydroxyl group at p-position in the aromatic ring is dueto high electron-releasing properties (positive mesomeric effect ishigher than negative inductive effect) and this activates the aro-matic ring. The compound 402 (IC50 ¼ 18.4 mg/mL) bearing anelectron-donating methoxy group at para position showed betterDPPH radical scavenging activity compared to 403 (IC50 ¼ 29.7 mg/mL). The compound with electron-poor nitro group exhibited lessactivity compared to compound 402 with methoxy group in thesame position.

Hussein [71] reported a synthesis of 2,3-dihydro-2-(3,4-dihydroxyphenyl) pyrazolo[5,1-b]quinazolin-9(1H)-one and testedfor their antioxidant potential. The tested compound 327 showedpromising antioxidant activity compared to the reference drug.

Al-Amiery and co-workers [141] synthesized two new quina-zoline derivatives and evaluated for their antioxidant activities. Thesynthesized compounds 352 and 353 were screened for in vitroantioxidant activity by DPPH, nitric oxide, and hydrogen peroxide.The scavenging method revealed good antioxidant activity for allsynthesized derivatives. Compound 352 exhibited good antioxidantactivity against DPPH and hydrogen peroxide, whereas 353exhibited good antioxidant activity against nitric oxide.

Revanasiddappa and co-workers [135] synthesized a novel classof N-substituted glycosmicine derivatives and examined for theirin vitro antioxidant activity by 2,2-diphenyl-1-picrylhydrazyl(DPPH) and superoxide radical scavenging assays. Among thetested samples, compounds 404e406 exhibited potent antioxidantactivity. The SAR studies revealed that the substitution nature andposition on the phenyl ring affected the antioxidant activityremarkably. It also showed that the electron-rich groups are morelikely to have higher antioxidant activity (Fig. 20).

Fig. 20. Compounds with antioxidant potential.

3.13. Antitrypanosomal activity

Patel et al. [155] described the discovery of potent trypanocidalcompounds that are based on established human EGFR inhibitorchemotypes. By starting with such “privileged” lead compounds,they have accelerated their antitrypanosomal lead discovery pro-gram by circumventing a need to run highthroughput screens.Indeed, in only a few optimization cycles they have identified apotent chemotype as a lead series for trypanosomiasis. Althoughcompound 407 has high calculated lipophilicity and molecularweight, its oral bioavailability lent the compound to furtherassessment in a mouse model of HAT, where modest effects wereobserved in controlling parasitemia, with concomitant life exten-sion of infected mice (Fig. 21).

3.14. Anti-streptococcal streptokinase expression activity

Yestrepsky et al. [156] reported a series of 5,6-dihydrobenzo[h]quinazolin-4(3H)-one analogues. All new compounds were evalu-ated for their ability to suppress SK expression via a chromogenicassay of plasmin activity. The analysis of these compounds resultedin the achievement of a greater than 35-fold improvement in ac-tivity (IC50 > 50 mMe1.3 mM) over compound 408 with optimumanalogue 409 (Fig. 22).

3.15. Agonistic activity

Park and co-workers [157] reported a series of novel 2,4-disubstituted quinazoline analogues and evaluated their agonisticactivity against human GPR119 receptor in a cell-based cAMP assay.The analogues bearing both (2-fluoro-4-methylsulfonyl)phenyl-amino and azabicyclic amine substituents 410-412 exhibited betterEC50 values than that of OEA though they appeared to be partialagonists. These results suggested that the combination of fluorineatom on benzene ring and azabicyclic amines proved to havesignificantly synergistic effect.

Fig. 21. Compound with antitrypanosomal activity.

Fig. 22. Structures of SK inhibitors.


Catarzi et al. [158] designed and synthesized a number of 5-oxo-pyrazolo[1,5-c]quinazoline analogues. All the reported compoundswere tested for their ability to displace specific [3H]DPCPX, [3H]ZM241385 and [125I]AB-MECA binding from cloned hA1, hA2A andhA2B receptors, respectively, stably expressed in CHO cells. Com-pounds were also tested at the hA2B subtype by measuring theirinhibitory effects on NECA-stimulated cAMP levels in CHO cellsstably transfected with the hA2B receptor. This study producedsome interesting compounds endowed with good hA3 receptoraffinity and high selectivity, being totally inactive at all the other ARsubtypes. In contrast, the corresponding 5-ammino derivatives donot bind or bind with very low affinity at the hA3 AR, the onlyexception being the 5-N-benzoyl compound 413 that shows a hA3Kivalue in the high micromolar range (Fig. 23).

3.16. Dihydrofolate reductase inhibitors

El-Subbagh and co-workers [122] designed and synthesized anew series of 2-heteroarylthio-6-substituted-quinazolin-4-oneanalogues and evaluated for their in vitro DHFR inhibitory activ-ity. Among the tested compounds, 414e416 proved to be the mostactive DHFR inhibitors with IC50 range of 0.3e1.0 mM. Structureeactivity relationship studies revealed that, the type of substituent atpositions 2-, 3- and 6- of the studied quinazolin-4-ones manipulatethe DHFR inhibition activity. In general, the 2-thiazolethio-sub-stituent on the quinazoline nucleus contributed to the DHFR inhi-bition activity more than the 2-phenylthio- or the 2-pyridinethio-moieties; also 3-phenyl-, and 6,7-dimethoxy substituent favor theactivity rather than 3-benzyl-, 6-methyl or 6-chloro functions(Fig. 24).

Fig. 23. Structures of compounds with agonistic activity.

3.17. Glucosidase inhibitors

Pottabathini and co-workers [159] designed quinazolinone-based non-carbohydrate mimetic inhibitors of the a-glucosidaseenzyme. C-6 substituted quinazolinone derivatives were screenedas a-glucosidase inhibitors by in silico high-throughput screening.Of these, three compounds were potentially active as a-glucosidaseinhibitors and showed activity with IC50 values <20 mM. Based onstructural novelty and desirable drug-like properties, 417 wasselected for structureeactivity relationship study, and thirteenanalogues were synthesized. Nine out of thirteen analogues actedas a-glucosidase inhibitors with IC50 values <10 mM and 418exhibited the most prominent activity. These lead compounds havedesirable physicochemical properties and are excellent candidatesfor further optimization (Fig. 25).

3.18. Kinase inhibitors

Dong and co-workers [58] designed and synthesized a series ofnovel azaspirocycle or azetidine substituted 4-anilinoquinazolinederivatives. The EGFR inhibitory activities and in vitro antitumorpotency of these newly synthesized compounds against two lungcancer cell lines HCC827 and A549 were evaluated. Most of thetarget compounds possess good inhibitory potency. In particular,compounds 419 with 2-oxa-6-azaspiro[3.4]octane substituent wasfound to possess higher EGFR inhibitory activities and similarantitumor potency comparing to the lead compound gefitinib withimproved water solubility.

Abadi and co-workers [61] described new quinazoline de-rivatives with an acrylamido group at position 6, and with variableanilino, sulfonamido and cycloalkylamino substituents at position4. All the synthesized acrylamide derivatives were tested for theirability to inhibit isolated recombinant wild type EGFR kinase. Thiswas followed by testing the cell growth inhibitory activity oncancer cell lines with wild type EGFR (breast cancer cell line SKBR3)and the gefitinib-resistant (H1975) NSCLC cell line harboring theL858R and T790M mutations. In addition, to correlate the cellgrowth inhibitionwith the mutant EGFR kinase inhibition, selectedcompounds were tested for their ability to inhibit EGFR auto-phosphorylation in the mutant EGFR expressing cell line (H1975).From the results, it can be seen that several compounds showsignificant inhibitory activity on thewild type as well as themutantEGFR kinase which is correlated with the cell growth inhibition.Compounds like 420e422were themost potent versus both cancercell lines having mutant and wild type EGFR.

Vasbinder and co-workers [160] discovered a novel series ofpotent mutant B-RafV600E selective kinase inhibitors based onquinazoline motif. The aminoquinazoline DFG-in class of com-pounds was shown to be potent and selective B-RafV600E inhibitorsthat evolved from a singleton hit identified from a kinase subsetscreening effort. From the results, it was further demonstrated thata lead compound from this series, 423 exhibits in vivo tumorgrowth inhibition in an A375 xenograft model.

Barlaam and co-workers [161] described the discovery ofAZD8931, an equipotent, reversible inhibitor of signaling by EGFR,HER2, and HER3 receptors. Docking studies based on amodel of theHER2 kinase domain helped to rationalize the increased HER2 ac-tivity seen with the methyl acetamide side chain present in com-pound 424. It also exhibits good selectivity among kinases outsidethe HER family and favorable physical properties and pharmaco-kinetics across species. It exhibits potent tumor growth inhibitionin various xenografts models, driven by EGFR alone or by EGFR andHER2. Compound 424 (also known as AZD8931) is currently inphase II clinical trials in patients with solid tumors.

Fig. 24. DHFR inhibitors.

Fig. 25. Glucosidase inhibitors.


Shen and Yu [162] designed and synthesized a series of novelconformationally constrained quinazoline analogues and evaluatedfor EGFR inhibition. The results analysis revealed that the mostpotent compounds 425 and 426 strongly inhibited the enzymaticactivities of wild-type EGFR kinase as well as clinical resistant EGFRmutant kinase. The kinase inhibitory efficiency of the compoundswere further validated byWestern Blot analysis for the activation ofEGFR. Further in vitro assay demonstrated that 425 and 426 areeffective against H1975 nonsmall cell lung cancer cells bearingEGFR[L858R/T790M], with potencies better than gefitinib. Further-more, an in vivo antitumor assay demonstrates that an oral oncedaily dose of 425 at 200 mg/kg produces considerable tumor in-hibition in the A431 xenograft model, as compared to gefitinib. Thepharmacokinetic studies indicated that 425 exhibits good phar-macokinetic properties.

Spencer and co-workers [163] synthesized a series of ferroceneanalogues based on a 6,7-dimethoxy-N-phenylquinazolin-4-aminederivatives. The synthesized compounds have been tested forin vitro anticancer activity against epidermal growth receptor(EGFR). Biological evaluation of the complexes showed them to beeffective EGFR inhibitors with micromolar or submicromolar po-tencies, which are significantly weaker than those of their relatedorganic prototypes. Docking studies have accounted for the goodin vitro EGFR inhibition observed for the ferrocene 427.

Xi et al. [164] reported a series of 5-anilinoquinazoline de-rivatives substituted by 1,3-disubstituted urea. All the newly syn-thesized compounds were evaluated for VEGFR-2 kinase inhibitionand antiproliferative activity against various cancer cells. The novel1-aryl, 3-aryl-disubstituted urea quinazolines were effectiveVEGFR-2 kinase inhibitors with in vitro IC50 values in the sub-micromolar range (428, IC50 12.0 nM), but showed a weak tomoderate inhibitory activity on cancer cells.

Singh and co-workers [165] synthesized a series of pyrido-quinazolines and tested for their in vitro epidermal growth factorreceptor (EGFR) tyrosine kinase inhibitory activity. Most of thesynthesized compounds displayed potent EGFRTK inhibitory ac-tivity like 429 and structurally halogenated derivatives had a pro-nounced effect in inhibiting EGFR internalization.

Xu et al. [166] synthesized two new series of compounds con-taining a 6-amino-substituted group or 6-acrylamide-substituted

group linked to a 4-anilinoquinazoline nucleus as potential EGFRinhibitors. These compounds proved efficient effects on anti-proliferative activity and EGFReTK inhibitory activity. Especially,N6-((5-bromothiophen-2-yl)methyl)-N4-(3-chlorophenyl)quinazo-line-4,6-diamine 430, showed the most potent inhibitory activity(IC50 ¼ 3.11 mM for HepG2, IC50 ¼ 0.82 mM for A549).

Li and co-workers [167] designed and synthesized twoseries of dithiocarbamic acid esters, 4-anilinoquinazoline-6-ylmethylcarbamodithioic acid esters and 3-cyano-4-anilinoquinolin-6-ylmethylcarbamodithioic acid esters. The ef-fect of the synthesized compounds on cell proliferation wasevaluated by MTT assay against three human cancer cell lines:MDA-MB-468, SK-BR-3 and HCT-116. Most of the compounds areequally or more potent than the positive control lapatinib. Threecompounds 431-433 were identified as dual inhibitors of theEGFR and ErbB-2 kinases and two compounds 434 and 435were identified as multi-target kinase inhibitors. Installationof the dithiocarbamic acid ester group at the 6-position of4-anilinoquinazoline or 3-cyano-4-anilinoquinoline couldimprove the inhibitory activity. Different dithiocarbamic acidester groups significantly affect the activities.

Zhang et al. [168] described a hybrid-design approach basedupon two privileged pharmacophores, namely 4-anilinoquinazoline and unsymmetrical diaryl urea, to successfullydeliver a novel series of multikinase inhibitors. Among the titlecompounds, 436-438 exhibited profound activity toward BRAF,BRAF V600E, VEGFR-2 and EGFR in biochemical screen. Further-more, it was observed that the potency for these kinases is gov-erned by both the R1-substituted urea moiety and the quinazolineC-7 side chain.

Zhu and co-workers [169] designed and synthesized a series ofnovel 4-alkoxyquinazoline derivatives and their biological activitieswere evaluated as potential inhibitors of vascular endothelialgrowth factor receptor 2 (VEGFR2). Among the tested compounds,439 displayed the most potent activity against VEGFR2 and MCF-7(breast cancer line) (IC50 ¼ 2.72 nM and IC50 ¼ 0.35 mM), beingcomparable with the positive control Tivozanib (IC50¼ 3.40 nM andIC50¼ 0.38 mM). Docking simulationwas also performed to positioncompound 439 into 4ASE active site, the result showed that com-pound 439 could bind well at the 4ASE active site.

Lü et al. [170] designed and synthesized a series of 4-anilinoquinazoline derivatives by modifications on the anilinering or at the 6-alkoxy site of the 6,7-dimethoxy-4-anilinoquinazoline pharmacophore for the inhibition of epidermalgrowth factor receptor (EGFR). The relative inhibition efficiency onEGFR of all as-prepared compounds were measured and ordered,and the IC50 values of highly active compoundswere determined byELISA. The results showed that compounds 440(IC50 ¼ 12.1�1.6 nM) and 441 (IC50 ¼ 13.6� 0.8 nM) were the mostpotent EGFR inhibitors in this class. The docking studies also rein-forced these observations and set a stage for further modification toobtain more potent anticancer compounds.


Abouzid and co-workers [171] designed and synthesized 4-anilinoquinazoline derivatives with enamine ester or urea moi-eties appended at the C-6 of quinazoline as additional hydrogenbond acceptor functions and evaluated for EGFR-TK and tumorgrowth inhibitory activities. Most of the synthesized compoundsdisplayed potent EGFR-TK inhibitory activity at 10 mM and amongthem, 6-ureido-anilinoquinazoline derivative 442 showed highestpotency with IC50 value of 0.061 mM. Furthermore, compound 442was also found to be the most selective candidate of the testedcompounds at 5 dose level screening against cell lines which are ofhigh EGFR expression [172].

Fan and co-workers [173] designed and developed a series ofnew lapatinib analogues as potent dual EGFR/HER-2 inhibitors withimproved druggability. The synthesized derivatives were testedagainst EGFR and HER-2 tyrosine kinase inhibition assay and cancercell proliferation inhibition assay and most of them exhibitedpotent affinity for EGFR or HER-2 kinase as well as excellent anti-proliferative activities. A potent EGFR/HER2 inhibitor N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2-(methylsulfinyl)ethyl-amino)methyl)furan-2-yl)quinazolin-4-amine 443 has beendiscovered. On the basis of its favorable solubility, pharmokineticprofiles and in vivo efficacies, 443 (selatinib) was progressed intofull development. It is currently in phase I clinical trials.

Zhang et al. [174] designed and synthesized a novel series ofanilinoquinazoline compounds with C-6 urea linked side chains asreversible inhibitors of epidermal growth factor receptor (EGFR).All compounds demonstrated good inhibition of EGFR wild type(EGFR wt) (IC50 ¼ 0.024e1.715 mM) and inhibited proliferation ofA431 cell line (IC50 ¼ 0.116e22.008 mM). From the biological re-sults, it is conceivable that compounds 444 and 445 almostcompletely blocked the phosphorylation of EGFR in A431 cell lineat 0.01 mM. Interestingly, all of the compounds also demonstratedmoderate inhibition of EGFR/T790M/L858R (IC50 ¼ 0.049e5.578 mM). In addition, compounds 446 and 447 blocked theautophosphorylation of EGFR in NCI-H1975 cells at high concen-tration (10 mM).

Li et al. [175] reported a series of 4,6-substituted-(dia-phenylamino)quinazolines as c-Src inhibitors and their biologicalactivity have also been evaluated. All the compounds displayedpotential antiproliferation activities with the IC50 values rangingfrom 3.42 to 118.81 mM in five human tumor cell lines. Particularly,compound 448 exhibited higher cytotoxicity against the tested fivetumor cell lines compared to the other small molecules. Generally,most of these compounds showed selectivity between theA549 cells and the other four cells, according to their correspondingIC50 values. In in vitro enzyme assay, the obtained results indicatedcompound 448 has remarkable inhibitory activity against c-Srckinasewith IC50 value of 27.3 nM, which could be comparable to thecontrol compounds. Furthermore, molecular docking and QSARstudy were also carried out to explore the binding modes and thestructure and activity relationship (SAR) of these derivatives.

Barreiro and co-workers [176] designed and synthesized a seriesof novel 2-chloro-4-anilino-quinazolines as EGFR and VEGFR-2dual inhibitors. The biological results obtained proved the poten-tial of 2-chloro-4-anilino-quinazoline derivatives as EGFR andVEGFR-2 dual inhibitors highlighting compound 449 which wasapproximately 7-fold more potent on VEGFR-2 and approximately11-fold more potent on EGFR compared to the prototype 450.Furthermore, SAR and docking studies allowed the identification ofpharmacophoric groups for both kinases.

Bursavich and co-workers [177] presented a series of novelMps1 inhibitors identified via de novo design effort. Structuredesign using molecular modeling, followed by conformational re-striction and scaffold hopping led to new quinazoline inhibitors.These new scaffolds 451-453 have been shown to be potent Mps1

inhibitor starting points with lowered MW, TPSA, and good ligandefficiencies (Figs. 26 and 27).

3.19. SUMO E1 inhibitors

Zhang and co-workers [178] reported the identification of qui-nazolinyloxy biaryl urea as a newclass of SUMO E1 inhibitors. Thesecompounds do not possess symmetric architecture and displaymoderate inhibition of sumoylation pathway. Among the testedcompounds, the activity of 454 was comparable with previouslyreported compounds and it inhibits sumoylation by preventing theformation of thioester intermediate. From the results, it can beconceived that this class of inhibitors can be used as starting pointsfor development of more potent SUMO E1 inhibitors (Fig. 28).

3.20. Topoisomerase inhibition

Passarella and co-workers [179] synthesized a series of evodi-amine derivatives. They have assayed the ability of these com-pounds to inhibit cell growth on three human tumor cell lines(H460, MCF-7 and HepG2) and evaluated the capacity to interferewith the catalytic activity of topoisomerase I both by the relaxationassay and the occurrence of the cleavable complex. The synthesizedcompounds did not possess promising activity at lowconcentration.

3.21. Phosphodiesterase inhibitors

Sánchez et al. [180] reported a new series of biphenyl-4-methylsulfanyl quinazoline derivatives and tested as PDE7 in-hibitors. Results showed interesting PDE7 inhibitory activity forsome of these quinazolines, with compounds 455e458 in the range0.7e0.9 mM. These compounds can be considered for future in vivoexperiments to develop more active compounds (Fig. 29).

3.22. Thymidylate synthase inhibitors

Stroud and co-workers [181] described a novel synthesis of N-[4-[2-Propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-L-g-glu-tamyl-D-glutamic acid 459 (BGC 945, now known as ONX 0801), asmall molecule thymidylate synthase (TS) inhibitor. This study alsodescribed an X-ray crystal structure of its complex with E. coli TSand 20-deoxyuridine-50-monophosphate, and a model for a similarcomplex with human TS (Fig. 30).

3.23. GlmU uridyltransferase inhibitors

Payne and co-workers [182] synthesized a series of quinazolinecompounds and evaluated against M. tuberculosis GlmU uridyl-transferase inhibitors. The most potent inhibitor 460 in this seriesexhibited an IC50 of 74 mM against GlmU uridyltransferase activityand serves as a promising starting point for the discovery of morepotent inhibitors (Fig. 31).

4. Agrochemical applications

Li et al. [63] reported a series of new 2-azolyl-3,4-dihydroquinazolines by direct cyclization of imidazole or 1,2,4-triazole with carbodiimides, which were obtained from aza-Wittig reaction of iminophosphorane with isocyanate. The pre-pared compounds were subjected to assess their fungicidal po-tential in vitro using agar diffusion and broth dilution assay againstPenicillium digitatum. The preliminary bioassay results demon-strated that most of the 2-imidazolyl-3,4-dihydroquinazolines

Fig. 26. Kinase inhibitors.


exhibited good to significant fungicidal activity whereas 2-triazolyl-3,4-dihydroquinazolines displayed low fungicidal activ-ity. Some of the 2-imidazolyl-3,4-dihydroquinazolines alsoexhibited strong binding interaction with the cytochrome P450-dependent sterol 14a-demethylase (CYP51). Among the synthe-sized derivatives, compound 461 showed the best fungicidal ac-tivity against P. digitatumwith IC50¼ 4.14 mg/mL and the best CYP51binding activity with Kd ¼ 0.34 mg/mL, both superior to those of theagricultural fungicide triadimefon.

Khan and co-workers [183] synthesized a series of new quina-zolinone derivatives and investigated their Larvicidal effect againstChironomus tentans Fabricius. Among the prepared analogues, mostof the compounds showed moderate Larvicidal potential at con-centration of 40 mg/mL. However, increasing the concentration upto 100 mg/mL led to an increase in the larvicidal activity. Interest-ingly, the methyl substitution in C-8 position as in compound 462increased the larvicidal activity up to 100% mortality. The mortality

result clearly indicates that presence of a methyl group in thephenyl ring is promising for enhanced larvicidal potential.

Zhou et al. [184] designed and synthesized a series of com-pounds incorporating dihydroquinazolinone moiety and evaluatedtheir insecticidal activities against oriental armyworm (Mythimnaseparata). Among the synthesized derivatives, most of the com-pounds showed moderate to high activities at the tested concen-trations. In particular, compounds 463 and 464 showed 80%larvicidal activities against oriental armyworm at the concentrationof 5 mg/L. The present study also explored the possible effects oftarget compounds on the high voltage-gated calcium channel andthe calcium channels in the endoplasmic reticulum in the centralneurons isolated from the third instar larvae of Spodoptera exiguausing whole-cell patch clamp and calcium imaging technique. Thepreliminary structureeactivity relationship of the title compoundsindicated that the small substituents in dihydroquinazolinonewere preferred. The calcium imaging technique experiments

Fig. 27. Kinase inhibitors (continued).


demonstrated that RyRs would be the possible action target of thisseries of novel compounds (Fig. 32).

5. Fluorescence properties

Mosselhi and co-workers [185] synthesized new [1,2,4]triazolo[5,1-b]- and [1,2,4]triazino[3,2-b]quinazoline nucleosides andinvestigated their fluorescence properties. Results obtained fromthe UVevisible and fluorescence studies revealed that the samplesincluding 465e467 can be applied for the manufacture of newmaterials with nonlinear optical (NLO) properties, as fluorescentmarkers, due to their strong fluorescence, or as light emitters inorganic light emitting devices (OLEDs) (Fig. 33).

Fig. 28. SUMO E1 inhibitor.

6. Miscellaneous literature appeared after manuscriptsubmission

Safaei et al. [186] reported a highly efficient and environmen-tally benign synthetic strategy to access quinazoline derivatives468 via the condensation of carbonyl compounds 183 with 2-

Fig. 29. Phosphodiesterase inhibitors.

Fig. 30. Thymidylate synthase inhibitor.

Fig. 31. GlmU uridyltransferase inhibitor.


aminobenzamide 152 using zirconium tetrakis(dodecylsulfate)[Zr(DS)4] as a highly efficient, reusable Lewis acid-surfactant-combined catalyst (Scheme 67). A broad range of substratesincluding aldehydes and ketones are successfully condensed with2-aminobenzamide and all reactions were completed in shorttimes and the products were obtained in good to excellent yields.The catalyst could be recycled and reused several times without anyloss of efficiency. This method also avoids the use of hazardouscatalysts or solvents, and briefly the promising points for the pre-sent methodology are efficiency, generality, high yield, short reac-tion time, clean reaction profile, ease of product isolation,simplicity, potential for recycling of the reaction medium andcatalyst, and finally agreement with the green chemistry protocols,which all make it a useful and attractive process for the synthesis ofquinazoline derivatives. Moreover, presented procedure has beenapplied successfully for the synthesis of spiro-quinazolinones de-rivatives (469e472) (Scheme 68).

Tajbakhsh and co-workers [187] were able to synthesize dihy-droquinazolinones 473 and quinazolinones 474 through an efficientcyclocondensation reaction of 2-aminobenzamide 152 with alde-hydes 206 catalyzed by H3PW12O40 as a recyclable catalyst inaqueous medium which has the advantages of high yields, shortreaction times, easy work-up, green procedure avoiding toxicorganic solvents, and the use of a readily available, inexpensive andrelatively non-toxic catalyst (Scheme 69).

Fig. 32. Compounds with a

He et al. [188] developed a novel palladium-catalyzed four-component carbonylative coupling system for the selective con-struction of 4(3H)-quinazolinones 477 in a one-pot fashion using 2-bromoanilines 475, trimethyl/triethyl orthoformate 476, andamines 204 under 10 bar of CO (Scheme 70). The desired productswere isolated in good yields. This process tolerates the presence ofvarious reactive functional groups and is very selective forquinazolinones.

Shi and co-workers [189] developed an unprecedented FeCl3-mediated, three-component domino strategy to access highlyfunctionalized pyrrolo[1,2-c]quinazolinones 480 in moderate toexcellent yields (Scheme 71). This method has advantages of mildconditions, simple work-up, as well as wide substrate scope, whichmakes it a powerful approach to the synthesis of diverse pyrrolo[1,2-c]quinazolinones. This cascade reaction involves 1,3-dipolarcycloaddition between azomethine ylides and allenoates, fol-lowed by intramolecular nucleophilic addition in the presence ofFeCl3.

Perumal and Kiruthika [190] reported a Cu(I)-catalyzed, inter-molecular protocol for the rapid construction of tetrahydroindolo[1,2-a]quinazolines 483 and indolo[1,2-a]quinazolines 484 in aone-pot fashion from the readily available gem-dibromovinylanilides 481 and sulfonamides 482 (Scheme 72).This process affords target products in shorter reaction time withhigh yields.

Kikuchi et al. [191] synthesized a series of new derivatives offebrifugine and evaluated for their in vitro and in vivo antima-larial activities against Plasmodium falciparum and their cyto-toxicity against mouse L929 cells. Among the screenedderivatives, tetrahydroquinazoline 485 exhibited potent antima-larial activity with a very high therapeutic selectivity both in vitroand in vivo.

Barreiro and co-workers [192] described the synthesis andbiological testing of a novel series of 2-chloro-4-anilino-quinazo-lines as EGFR and VEGFR-2 dual inhibitors. The biological dataobtained proved the potential of 2-chloro-4-anilino-quinazolinederivatives as EGFR and VEGFR-2 dual inhibitors, highlightingcompound 486, which was approximately 7-fold more potent onVEGFR-2 and approximately 11-fold more potent on EGFR. SAR anddocking studies allowed the identification of pharmacophoricgroups for both kinases and demonstrated the importance of ahydrogen bond donor at the para position of the aniline moiety forinteraction with conserved Glu and Asp amino acids in EGFR andVEGFR-2 binding sites.

�Spulák et al. [193] described a novel group of potential bron-chodilatory compounds the efficacy of which against isolated rattrachea is substantially higher than those of the vasicinone lead andtheophylline. In addition, in vitro and in vivo toxicity studies bothprovided promising results. Finally, preliminary evaluation of apossible mode of action indicated that the most interesting alkyl-sulfanyl derivative 487 is the promising structure with highestbronchodilatory potential (Fig. 34).

grochemical potential.

Fig. 33. Compounds with non-linear optical properties.

Scheme 67.

Scheme 68.


Scheme 69.

Scheme 70.


7. Conclusions and perspectives

Drug development has been a principal driving force in therapidmaturation of the field of medicinal chemistry during the pastseveral decades, and during this period, a significant attention ofthe scientific community has been paid to the development ofintriguing and challenging molecular architectures of nitrogencontaining heterocyclic compounds in (bio)organic chemistry. Inthis review, we have introduced readers to a broad range of novel,efficient, extremely mild, and operationally simple syntheticmethods to access a library of highly functionalized quinazoline

Scheme

and quinazolinone scaffolds through readily available and cheapstarting materials. Several strategies including metal-catalyzedreactions, MCR, and microwave-irradiation and conventionalheating methods have been successfully employed to achieve thesediversely decorated skeletons which are of significant importancefor pharmaceutical as well as agrochemical industries. This article isalso focused on the discussion of reaction conditions, substratescope and development of new reaction types. Apart fromremarkable synthetic progress, these scaffolds have been screenedagainst numerous biological targets and showed significant bio-activities. Several quinazoline- and quinazolinone-based drugs

71.

Fig. 34. Compounds with miscellaneous activities.

Scheme 72.


have already made their way to clinics and are successfully oper-ational against various disorders. The structureeactivity relation-ship of the reported compounds revealed that the choice of asuitable substitution pattern including electron-donating, electron-withdrawing as well as some heterocyclic moieties, on the basicskeleton plays a key role in regulating the biological potential of thesynthesized compounds. Furthermore, due to the simple syntheticmethods enabling to construct core motifs of numerous marketeddrugs, we sincerely hope that this article will stimulate furtherresearch in current domain by encouraging scientists to designnovel approaches with their diverse exploitation of biological ac-tivities, and garner the interest of the scientific community for awhile.

References

[1] V. Polshettiwar, R.S. Varma, Greener and sustainable approaches to thesynthesis of pharmaceutically active heterocycles, Current Opinion in DrugDiscovery & Development 10 (2007) 723e737.

[2] A. Padwa, S.K. Bur, The domino way to heterocycles, Tetrahedron 63 (2007)5341e5378.

[3] D.M. D’Souza, T.J. Muller, Multi-component syntheses of heterocycles bytransition-metal catalysis, Chemical Society Reviews 36 (2007) 1095e1108.

[4] N.A. McGrath, M. Brichacek, J.T. Njardarson, A graphical journey of innovativeorganic architectures that have improved our lives, Journal of Chemical Ed-ucation 87 (2010) 1348e1349.

[5] S. Dadiboyena, Cycloadditions and condensations as essential tools in spi-ropyrazoline synthesis, European Journal of Medicinal Chemistry 63 (2013)347e377.

[6] R.W. DeSimone, K.S. Currie, S.A. Mitchell, J.W. Darrow, D.A. Pippin, Privilegedstructures: applications in drug discovery, Combinatorial Chemistry & HighThroughput Screening 7 (2004) 473e494.

[7] P.D. Leeson, B. Springthorpe, The influence of drug-like concepts on decision-making in medicinal chemistry, Nature Reviews Drug Discovery 6 (2007)881e890.

[8] Merck Index, 13th ed., Merck Publishing Group, Rahway, NJ, 2001. No 8141.[9] P.S. Reddy, P.P. Reddy, T. Vasantha, A review on 2-heteryl and heteroalkyl-

4(3H)quinazolinones, Heterocycles 60 (2003) 183e226.[10] G.A. El-Hiti, Synthesis of substituted quinazolin-4(3H)-ones and quinazolines

via directed lithiation, Heterocycles 53 (2000) 1839e1868.[11] G.A. El-Hiti, M.F. Abdel-Megeed, Synthesis of glycosides containing quina-

zolin-4(3H)-one ring system, Heterocycles 65 (2005) 3007e3041.[12] P. Verhaeghe, N. Azas, M. Gasquet, S. Hutter, C. Ducros, M. Laget, S. Rault,

P. Rathelot, P. Vanelle, Synthesis and antiplasmodial activity of new 4-aryl-2-trichloromethylquinazolines, Bioorganic & Medicinal Chemistry Letters 18(2008) 396e401.

[13] (a) L.F. Kuyper, D.P. Baccanari, M.L. Jones, R.N. Hunter, R.L. Tansik, S.S. Joyner,C. Boytos, S.K. Rudolph, V. Knick, H.R. Wilson, J.M. Caddell, H.S. Friedman,J.C.W. Comley, J.N. Stables, High-affinity inhibitors of dihydrofolate reduc-tase: antimicrobial and anticancer activities of 7,8-dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with small molecular size, Journal ofMedicinal Chemistry 39 (1996) 892e903;(b) B. Maggio, G. Daidone, D. Raffa, S. Plescia, L. Mantione, V.M.C. Cutuli,N.G. Mangano, A. Caruso, Synthesis and pharmacological study of ethyl 1-methyl-5-(substituted 3,4-dihydro-4-oxoquinazolin-3-yl)-1H-pyrazole-4-acetates, European Journal of Medicinal Chemistry 36 (2001) 737e742;(c) G. Grover, S.G. Kini, Synthesis and evaluation of new quinazolone de-rivatives of nalidixic acid as potential antibacterial and antifungal agents,European Journal of Medicinal Chemistry 41 (2006) 256e262.

[14] (a) V. Alagarsamy, V.R. Solomon, R.V. Sheorey, R. Jayakumar, Synthesis of 3-(3-Ethylphenyl)-2-substituted amino-3H-quinazolin-4-ones as novel class ofanalgesic and anti-inflammatory agents, Chemical Biology & Drug Design 73(2009) 471e479;(b) R.A. Smits, M. Adami, E.P. Istyastono, O.P. Zuiderveld, C.M.E. van Dam,F.J.J. de Kanter, A. Jongejan, G. Coruzzi, R. Leurs, I.J.P. de Esch, Synthesis andQSAR of quinazoline sulfonamides as highly potent human histamine H4receptor inverse agonists, Journal of Medicinal Chemistry 53 (2010) 2390e2400;(c) A. Kumar, C.S. Rajput, S.K. Bhati, Synthesis of 3-[4’-(p-chlorophenyl)-thiazol-2-yl]-2-[(substituted azetidinonethiazolidinone)-aminomethyl]-6-bromoquinazolin-4-ones as anti-inflammatory agent, Bioorganic & Medici-nal Chemistry 15 (2007) 3089e3096;(d) V. Alagarsamy, R. Solomon, M. Murugan, K. Dhanabal, P. Parthiban,G.V.J. Anjana, Design and synthesis of 3-(4-ethylphenyl)-2-substitutedamino-3H-quinazolin-4-ones as a novel class of analgesic and anti-inflammatory agents, Journal of Enzyme Inhibition and Medicinal Chemis-try 23 (2008) 839e847;(e) S.K. Pandey, A. Singh, A. Singh, Nizamuddin, Antimicrobial studies ofsome novel quinazolinones fused with [1,2,4]-triazole, [1,2,4]-triazine and[1,2,4,5]-tetrazine rings, European Journal of Medicinal Chemistry 44 (2009)1188e1197.

[15] (a) H. Georgey, N. Abdel-Gawad, S. Abbas, Synthesis and anticonvulsant ac-tivity of some quinazolin-4-(3H)-one derivatives, Molecules 13 (2008)2557e2569;(b) V.K. Archana Srivastava, A. Kumar, Synthesis of newer thiadiazolyl andthiazolidinonyl quinazolin-4(3H)-ones as potential anticonvulsant agents,European Journal of Medicinal Chemistry 37 (2002) 873e882;(c) M. Zappalá, S. Grasso, N. Micale, G. Zuccalá, F.S. Menniti, G. Ferreri, G. DeSarro, C. De Micheli, 1-Aryl-6,7-methylenedioxy-3H-quinazolin-4-ones asanticonvulsant agents, Bioorganic & Medicinal Chemistry Letters 13 (2003)4427e4433;(d) V. Jatav, P. Mishra, S. Kashaw, J.P. Stables, CNS depressant and anticon-vulsant activities of some novel 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones, European Journal of Medicinal Chemistry 43(2008) 1945e1954;(e) S.K. Kashaw, V. Kashaw, P. Mishra, N.K. Jain, J.P. Stables, CNS depressantand anticonvulsant activities of some new bioactive 1-(4-substituted-

http://refhub.elsevier.com/S0223-5234(14)00125-1/sref1









































http://refhub.elsevier.com/S0223-5234(14)00125-1/bib13a







http://refhub.elsevier.com/S0223-5234(14)00125-1/bib13b





http://refhub.elsevier.com/S0223-5234(14)00125-1/bib13c



















http://refhub.elsevier.com/S0223-5234(14)00125-1/bib14d






http://refhub.elsevier.com/S0223-5234(14)00125-1/bib14e


























phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea, European Jour-nal of Medicinal Chemistry 44 (2009) 4335e4343.

[16] (a) M.A.H. Ismail, S. Barker, D.A. Abau El Ella, K.A.M. Abouzid, R.A. Toubar,M.H.J. Todd, Design and synthesis of new tetrazolyl- and carboxy-biphenylylmethyl quinazoline derivatives as angiotensin II AT1 receptorantagonists, Medicinal Chemistry 49 (2006) 1526e1535;(b) K.S. Jain, J.B. Bariwal, M.K. Kathiravan, M.S. Phoujdar, R.S. Sahne,B.S. Chauhan, A.K. Shah, M.R. Yadav, Recent advances in selective alpha1-adrenoreceptor antagonists as antihypertensive agents, Bioorganic & Me-dicinal Chemistry 16 (2008) 4759e4800;(c) V. Alagarsamy, U.S. Pathak, Synthesis and antihypertensive activity ofnovel 3-benzyl-2-substituted-3H-[1,2,4]triazolo[5,1-b]quinazolin-9-ones,Bioorganic & Medicinal Chemistry 15 (2007) 3457e3462.

[17] M.S. Malamas, J. Millen, Quinazoline acetic acids and related analogues asaldose reductase inhibitors, Journal of Medicinal Chemistry 34 (1991) 1492e1503.

[18] M. Decker, Novel inhibitors of acetyl- and butyrylcholinesterase derivedfrom the alkaloids dehydroevodiamine and rutaecarpine, European Journalof Medicinal Chemistry 40 (2005) 305e313.

[19] (a) P. Mani Chandrika, T. Yakaiah, A. Raghu Ram Rao, B. Narsaiah, N. ChakraReddy, V. Sridhar, J. Venkateshwara Rao, Synthesis of novel 4,6-disubstitutedquinazoline derivatives, their anti-inflammatory and anti-cancer activity(cytotoxic) against U937 leukemia cell lines, European Journal of MedicinalChemistry 43 (2008) 846e852;(b) D. Giardin, D. Martarelli, G. Sagratini, P. Angeli, D. Ballinari, U. Gulini,C. Melchiorre, E. Poggesi, P. Pompei, Doxazosin-related a1-adrenoceptorantagonists with prostate antitumor activity, Journal of Medicinal Chemistry52 (2009) 4951e4954;(c) B. Marvania, P.-C. Lee, R. Chaniyara, H.-J. Dong, S. Suman, R. Kakadiya, T.-C. Chou, T.-C. Lee, A. Shah, T.-L. Su, Design, synthesis and antitumor evalu-ation of phenyl N-mustard-quinazoline conjugates, Bioorganic & MedicinalChemistry 19 (2011) 1987e1998;(d) H.M. Shallal, W.A. Russu, Discovery, synthesis, and investigation of theantitumor activity of novel piperazinylpyrimidine derivatives, EuropeanJournal of Medicinal Chemistry 46 (2011) 2043e2057;(e) A. Chilin, M.T. Conconi, G. Marzaro, A. Guiotto, L. Urbani, F. Tonus,P. Parnigotto, Exploring epidermal growth factor receptor (EGFR) inhibitorfeatures: the role of fused dioxygenated rings on the quinazoline scaffold,Journal of Medicinal Chemistry 53 (2010) 1862e1866;(f) I. Sagiv-Barfi, E. Weiss, A. Levitzki, Design, synthesis, and evaluation ofquinazoline T cell proliferation inhibitors, Bioorganic & Medicinal Chemistry18 (2010) 6404e6413.

[20] (a) A. Rosowsky, J.E. Wright, C.M. Vaidya, R.A. Forsch, The effect of side-chain,para-aminobenzoyl region, and B-ring modifications on dihydrofolatereductase binding, influx via the reduced folate carrier, and cytotoxicity ofthe potent nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine, Pharmacology Thera-peutics 85 (2000) 191e205;(b) A. Gangjee, M. Kothare, R.L. Kisliuk, The synthesis of novel nonclassicalreversed bridge quinazoline antifolates as inhibitors of thymidylate syn-thase, Journal of Heterocyclic Chemistry 37 (2000) 1097e1102.

[21] (a) A. Levitzky, Protein kinase inhibitors as a therapeutic modality, Accountsof Chemical Research 36 (2003) 462e469;(b) A. Garofalo, L. Goossens, A. Lemoine, S. Ravez, P. Six, M. Howsam, A. Farce,P. Depreux, [4-(6,7-Disubstituted quinazolin-4-ylamino)phenyl] carbamicacid esters: a novel series of dual EGFR/VEGFR-2 tyrosine kinase inhibitors,Medicinal Chemistry Communications 2 (2011) 65e72;(c) H. Nakamura, R. Horikoshi, T. Usui, H.S. Ban, Selective inhibition of EGFR andVEGFR2 tyrosine kinases controlled by a boronic acid substituent on 4-anilinoquinazolines, Medicinal Chemistry Communications 1 (2010) 282e286;(d) R.-D. Li, X. Zhang, Q.-Y. Li, Z.-M. Ge, R.-T. Li, Novel EGFR inhibitors preparedby combination of dithiocarbamic acid esters and 4-anilinoquinazolines, Bio-organic & Medicinal Chemistry Letters 21 (2011) 3637e3640;(e) O. Cruz-López, A. Conejo-García, M.C. Núñez, M. Kimatrai, M.E. García-Rubiño, F. Morales, V. Gómez-Pérez, J.M. Campos, Novel substituted quinazo-lines for potent EGFR tyrosine kinase inhibitors, Current Medicinal Chemistry18 (2011) 943e963.

[22] G.M. Chinigo, M. Paige, S. Grindrod, E. Hamel, S. Dakshanamurthy,M. Chruszcz, W. Minor, M.L. Brown, Asymmetric synthesis of 2,3-dihydro-2-arylquinazolin-4-ones: methodology and application to a potent fluorescenttubulin inhibitor with anticancer activity, Journal of Medicinal Chemistry 51(2008) 4620e4631.

[23] (a) T. Sardon, T. Cottin, J. Xu, A. Giannis, I. Vernos, Development and bio-logical evaluation of a novel Aurora A kinase inhibitor, ChemBioChem 10(2009) 464e478;(b) D. Bebbington, H. Binch, J.-D. Charrier, S. Everitt, D. Fraysse, J. Golec,D. Kay, R. Knegtel, C. Mak, F. Mazzei, A. Miller, M. Mortimore, M. O’Donnell,S. Patel, F. Pierard, J. Pinder, J. Pollard, S. Ramaya, D. Robinson, A. Rutherford,J. Studley, J. Westcott, The discovery of the potent aurora inhibitor MK-0457(VX-680), Bioorganic & Medicinal Chemistry Letters 19 (2009) 3586e3592.

[24] S.L. Cao, Y.Wang, L. Zhu, J. Liao, Y.W.Guo, L.L. Chen, H.Q. Liu, X. Xu, Synthesis andcytotoxic activity of N-((2-methyl-4(3H)-quinazolinon-6-yl)methyl)dithiocar-bamate, European Journal of Medicinal Chemistry 45 (2010) 3850e3857.

[25] (a) N. Sirisoma, S. Kasibhatla, A. Pervin, H. Zhang, S. Jiang, J.A. Willardsen,M.B. Anderson, V. Baichwal, G.G. Mather, K. Jessing, R. Hussain, K. Hoang,

C.M. Pleiman, B. Tseng, J. Drewe, S.X. Cai, Discovery of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine (EP128265, MPI-0441138)as a potent inducer of apoptosis with high in vivo activity, Journal of Me-dicinal Chemistry 51 (2008) 4771e4779;(b) K.A. Olaussen, F. Commo, M. Tailler, L. Lacroix, I. Vitale, S.Q. Raza,C. Richon, P. Dessen, V. Lazar, J.C. Soria, G. Kroemer, Synergistic proapoptoticeffects of the two tyrosine kinase inhibitors pazopanib and lapatinib onmultiple carcinoma cell lines, Oncogene 28 (2009) 4249e4260.

[26] (a) C. Wattanapiromsakul, P.I. Forster, P.G. Waterman, Alkaloids and limo-noids from Bouchardatia neurococca: systematic significance, Phytochem-istry 64 (2003) 609e615;(b) Z.-Z. Ma, Y. Hano, T. Nomura, Y.-J. Chen, Alkaloids and phenylpropanoidsfrom Peganum nigellastrum, Heterocycles 46 (1997) 541e546;(c) D. Yonghong, X. Rensheng, Y. Yang, A new quinazolone alkaloid fromleaves of Dichroa febrifuga, Journal of Chinese Pharmaceutical Sciences 9(2000) 116e118;(d) S.B. Mhaske, N.P. Argade, The chemistry of recently isolated naturallyoccurring quinazolinone alkaloids, Tetrahedron 62 (2006) 9787e9826.

[27] N.M. Abdel Gawad, H.H. Georgey, R.M. Youssef, N.A. El-Sayed, Synthesis andantitumor activity of some 2,3-disubstituted quinazolin-4(3H)-ones and 4,6-disubstituted-1,2,3,4-tetrahydroquinazolin-2H-ones, European Journal ofMedicinal Chemistry 45 (2010) 6058e6067.

[28] D.W. Fry, A.J. Kraker, A. McMichael, L.A. Ambroso, J.M. Nelson, W.R. Leopold,R.W. Connors, A.J. Bridges, A specific inhibitor of the epidermal growth factorreceptor tyrosine kinase, Science 265 (1994) 1093e1095.

[29] A. Lewerenz, S. Hentschel, Z. Vissiennon, S. Michael, K. Nieber, A3 receptors incortical neurons: pharmacological aspects and neuroprotection duringhypoxia, Drug Development Research 58 (2003) 420e427.

[30] N. Malecki, P. Carato, G. Rigo, J.F. Goossens, R. Houssin, C. Bailly,J.P. Henichart, Synthesis of condensed quinolines and quinazolines as DNAligands, Bioorganic & Medicinal Chemistry 12 (2004) 641e647.

[31] Merck Index, 13th ed., Merck Publishing Group, Rahway, NJ, 2001. No. 7803.[32] Merck Index, 13th ed., Merck Publishing Group, Rahway, NJ, 2001. No. 1475.[33] Merck Index, 13th ed., Merck Publishing Group, Rahway, NJ, 2001. No. 3466.[34] (a) S. Mohri, Research and development of synthetic processes for pharma-

ceuticals: pursuit of rapid, inexpensive, and good processes, Journal ofSynthetic Organic Chemistry, Japan 59 (2001) 514e515.

[35] H.N. Seo, J.Y. Choi, Y.J. Choe, Y. Kim, H. Rhim, S.H. Lee, J. Kim, D.J. Joo, J.Y. Lee,Discovery of potent T-type calcium channel blocker, Bioorganic & MedicinalChemistry Letters 17 (2007) 5740e5743.

[36] (a) A. Witt, J. Bergman, Recent developments in the field of quinazolinechemistry, Current Organic Chemistry 7 (2003) 659e677;(b) D.J. Connolly, D. Cusack, T.P. O’Sullivan, P.J. Guiry, Synthesis of quinazo-linones and quinazolines, Tetrahedron 61 (2005) 10153e10202;(c) J.P. Michael, Quinoline, quinazoline and acridone alkaloids, NaturalProduct Reports 21 (2004) 650e668;(d) J.P. Michael, Quinoline, quinazoline and acridone alkaloids, NaturalProduct Reports 20 (2003) 476e493;(e) J.P. Michael, Quinoline, quinazoline and acridone alkaloids, NaturalProduct Reports 19 (2002) 742e760;(f) J.P. Michael, Quinoline, quinazoline and acridone alkaloids, NaturalProduct Reports 18 (2001) 543e559;(g) J.P. Michael, Quinoline, quinazoline and acridone alkaloids, NaturalProduct Reports 17 (2000) 603e620;(h) J.P. Michael, Quinoline, quinazoline and acridone alkaloids, NaturalProduct Reports 16 (1999) 697e709;(i) J.P. Michael, Quinoline, quinazoline and acridone alkaloids, NaturalProduct Reports 15 (1998) 595e606;(j) J.P. Michael, Quinoline, quinazoline and acridone alkaloids, NaturalProduct Reports 14 (1997) 11e20;(k) Z. Ma, Y. Hano, T. Nomura, Heterocycles 65 (2005) 2203.

[37] (a) W.L.F. Armarego, in: A.R. Katrizky, A.J. Boulton (Eds.), Adv. Heterocycl.Chem, 24, Academic, NewYork, 1979, p. 1;(b) D.J. Brown, in: A.J. Boulton, A. McKillop (Eds.), Comprehensive Hetero-cyclic Chemistry, 3 (2B), Pergamon Press, Oxford, 1984, p. 57;(c) D.J. Brown, Quinazolines, in: The Chemistry of Heterocyclic Compounds,Suppl. 1, 55Wiley, New York, 1996.

[38] (a) I. Khan, S. Ali, S. Hameed, N.H. Rama, M.T. Hussain, A. Wadood, R. Uddin,Z. Ul-Haq, A. Khan, S. Ali, M.I. Choudhary, Synthesis, antioxidant activitiesand urease inhibition of some new 1,2,4-triazole and 1,3,4-thiadiazole de-rivatives, European Journal of Medicinal Chemistry 45 (2010) 5200e5207;(b) I. Khan, M. Hanif, A.A. Khan, N.H. Rama, M.T. Hussain, M.A.S. Aslam,J. Iqbal, Synthesis, acetylcholinesterase and alkaline phosphatase inhibitionof some new 1,2,4-Triazole and 1,3,4-Thiadiazole derivatives, AustralianJournal of Chemistry 65 (2012) 1413e1419;(c) I. Khan, A. Ibrar, M. Waqas, J.M. White, Synthesis, X-ray crystallographicstudies and antibacterial screening of 1-(5-(4-Chlorophenyl)thiazol-2-yl)Hydrazine hydrobromide, Physical Review & Research International 3 (2013)10e17;(d) I. Khan, A. Ibrar, N. Abbas, Triazolothiadiazoles and triazolothiadiazines -biologically attractive scaffolds, European Journal of Medicinal Chemistry 63(2013) 854e868;(e) A. Ibrar, I. Khan, N. Abbas, Structurally diversified heterocycles andrelated privileged scaffolds as potential urease inhibitors: a brief overview,Archiv der Pharmazie e Chemistry in Life Sciences 346 (2013) 423e446;



















































http://refhub.elsevier.com/S0223-5234(14)00125-1/bib19f

































































































































http://refhub.elsevier.com/S0223-5234(14)00125-1/bib36g



http://refhub.elsevier.com/S0223-5234(14)00125-1/bib36h



http://refhub.elsevier.com/S0223-5234(14)00125-1/bib36i



http://refhub.elsevier.com/S0223-5234(14)00125-1/bib36j



http://refhub.elsevier.com/S0223-5234(14)00125-1/bib36k
































(f) I. Khan, A. Ibrar, N. Abbas, Oxadiazoles as privileged motifs for promisinganticancer leads: recent advances and future prospects, Archiv der Phar-mazie e Chemistry in Life Sciences 347 (2014) 1e20;(g) M. Hanif, I. Khan, N.H. Rama, S. Noreen, M.I. Choudhary, P.G. Jones,M. Iqbal, Synthesis, crystal structure and b-glucuronidase inhibition activityof some new hydrazinecarboxamides and their 1,2,4-triazole derivatives,Medicinal Chemistry Research 21 (2012) 3885e3896;(h) A. Saeed, N.A. Al-Masoudi, M. Latif, Synthesis and antiviral activity of newsubstituted methyl [2-(arylmethylene-hydrazino)-4-oxo-thiazolidin-5-ylidene]acetates, Archiv der Pharmazie e Chemistry in Life Sciences 346(2013) 618e625;(i) S. Ali, A. Saeed, N. Abbas, M. Shahid, M. Bolte, J. Iqbal, Design, synthesisand molecular modelling of novel methyl[4-oxo-2-(aroylimino)-3-(substituted phenyl)thiazolidin-5-ylidene]acetates as potent and selectivealdose reductase inhibitors, Medicinal Chemistry Communications 3 (2012)1428e1434.

[39] X. Yang, Y. Jin, H. Liu, Y. Jiang, H. Fu, Easy and efficient one-pot synthesis ofpyrazolo[1,5-c]quinazolines under mild copper-catalyzed conditions, RSCAdvances 2 (2012) 11061e11066.

[40] R. Adepu, R. Sunke, C.L.T. Meda, D. Rambabu, G.R. Krishna, C.M. Reddy,G.S. Deora, K.V.L. Parsa, M. Pal, Facile assembly of two 6-membered fused N-heterocyclic rings: a rapid access to novel small molecules via Cu-mediatedreaction, Chemical Communications 49 (2013) 190e192.

[41] D. Rocchi, J.F. González, J.C. Menéndez, Microwave-assisted, sequential four-component synthesis of polysubstituted 5,6-dihydroquinazolinones fromacyclic precursors and a mild, halogenation-initiated method for theiraromatization under focused microwave irradiation, Green Chemistry 15(2013) 511e517.

[42] G. Qiu, Y. Lu, J. Wu, A concise synthesis of 4-imino-3,4-dihydroquinazolin-2-ylphosphonates via a palladium-catalyzed reaction of carbodiimide, iso-cyanide, and phosphite, Organic & Biomolecular Chemistry 11 (2013) 798e802.

[43] J. Fang, J. Zhou, Z. Fang, Synthesis of 2-substituted quinazolines via iridiumcatalysis, RSC Advances 3 (2013) 334e336.

[44] Y. Lv, Y. Li, T. Xiong, W. Pu, H. Zhang, K. Sun, Q. Liu, Q. Zhang, Copper-catalyzed annulation of amidines for quinazoline synthesis, Chemical Com-munications 49 (2013) 6439e6441.

[45] X. Su, C. Chen, Y. Wang, J. Chen, Z. Lou, M. Li, One-pot synthesis of quina-zoline derivatives via [2þ2þ2] cascade annulation of diaryliodonium saltsand two nitriles, Chemical Communications 49 (2013) 6752e6754.

[46] S.-J. Yan, Y. Dong, Q. Peng, Y.-X. Fan, J.-H. Zhang, J. Lin, Synthesis of polyhalo2-aryl-4-aminoquinazolines and 3-amino-indazoles as anti-cancer agents,RSC Advances 3 (2013) 5563e5569.

[47] C. Wang, L. Zhang, A. Ren, P. Lu, Y. Wang, Cu-catalyzed synthesis of tryp-tanthrin derivatives from substituted indoles, Organic Letters 15 (2013)2982e2985.

[48] H. Wang, X. Cao, F. Xiao, S. Liu, G.-J. Deng, Iron-catalyzed one-pot 2,3-diarylquinazolinone formation from 2-Nitrobenzamides and alcohols,Organic Letters 15 (2013) 4900e4903.

[49] (a) Y.-F. Wang, F.-L. Zhang, S. Chiba, Oxidative radical skeletal rearrangementinduced by molecular oxygen: synthesis of quinazolinones, Organic Letters15 (2013) 2842e2845;(b) A. Carocci, A. Catalano, F. Corbo, A. Duranti, R. Amoroso, C. Franchini,G. Lentini, V. Tortorella, Stereospecific synthesis of mexiletine and relatedcompounds: Mitsunobu versus Williamson reaction, Tetrahedron: Asym-metry 11 (2000) 3619e3634;(c) L.A. Sorbera, J. Bolós, N. Serradell, M. Bayés, Ispinesib mesilate. Antimitoticdrug, KSP inhibitor, Drugs of the Future 31 (2006) 778e787.

[50] X. Ji, Y. Zhou, J. Wang, L. Zhao, H. Jiang, H. Liu, Au(I)/Ag(I)-catalyzed cascadeapproach for the synthesis of Benzo[4,5]imidazo[1,2-c]pyrrolo[1,2-a]quina-zolinones, Journal of Organic Chemistry 78 (2013) 4312e4318.

[51] D.-S. Chen, G.-L. Dou, Y.-L. Li, Y. Liu, X.-S. Wang, Copper(I)-Catalyzed syn-thesis of 5-Arylindazolo[3,2-b]quinazoline-7(5H)-one via Ullmann-type re-action, Journal of Organic Chemistry 78 (2013) 5700e5704.

[52] S.I. Mirallai, M.J. Manos, P.A. Koutentis, The one-step conversion of 2-amino-N’-arylbenzamidines into 3-aryl-4-imino-3,4-dihydroquinazoline-2-carbonitriles using 4,5-dichloro-1,2,3-dithiazolium chloride, Journal ofOrganic Chemistry 78 (2013) 9906e9913.

[53] S. Guo, J. Wang, X. Fan, X. Zhang, D. Guo, Synthesis of pyrazolo[1,5-c]qui-nazoline derivatives through copper-catalyzed tandem reaction of 5-(2-Bromoaryl)-1H-pyrazoles with carbonyl compounds and aqueousammonia, Journal of Organic Chemistry 78 (2013) 3262e3270.

[54] R. Rohlmann, T. Stopka, H. Richter, O.G. Mancheño, Iron-catalyzed oxidativetandem reactions with TEMPO oxoammonium salts: synthesis of dihy-droquinazolines and quinolines, Journal of Organic Chemistry 78 (2013)6050e6064.

[55] S. Venkateswarlu, M. Satyanarayana, P. Ravikiran, V. Siddaiah, Reaction ofimidoformates with anthranilates: facile, one-pot, three-component syn-thesis of 8H-Quinazolino[4,3-b]quinazolin-8-ones, Journal of HeterocyclicChemistry 50 (2013) 1089e1093.

[56] A. Sharma, V. Luxami, K. Paul, Synthesis, single crystal and antitumor ac-tivities of benzimidazoleequinazoline hybrids, Bioorganic & MedicinalChemistry Letters 23 (2013) 3288e3294.

[57] L. Wu, C. Zhang, W. Li, Regioselective synthesis of 6-aryl-benzo[h][1,2,4]-triazolo[5,1-b] quinazoline-7,8-diones as potent antitumoral agents, Bio-organic & Medicinal Chemistry Letters 23 (2013) 5002e5005.

[58] F. Zhao, Z. Lin, F. Wang, W. Zhao, X. Dong, Four-membered heterocycles-containing 4-anilino-quinazoline derivatives as epidermal growth factorreceptor (EGFR) kinase inhibitors, Bioorganic & Medicinal Chemistry Letters23 (2013) 5385e5388.

[59] (a) M. Dukat, K. Alix, J. Worsham, S. Khatri, M.K. Schulte, 2-amino-6-chloro-3,4-dihydroquinazoline: a novel 5-HT receptor antagonist with antidepres-sant character, Bioorganic & Medicinal Chemistry Letters 23 (2013) 5945e5948;(b) A.A. Rahman, M.K. Daoud, M. Dukat, K. Herrick-Davis, A. Purohit,M. Teitler, A.T. do Amaral, A. Malvezzi, R.A. Glennon, Conformationally-Restricted analogues and partition coefficients of the 5-HT3 serotonin re-ceptor ligands meta-Chlorophenylbiguanide (mCPBG) and meta-Chlorophenylguanidine (mCPG), Bioorganic & Medicinal Chemistry Letters13 (2003) 1119e1123. Bioorg. Med. Chem. Lett. Corrigendum to the above,22 (2012) 6526;(c) J.A. Grosso, D.E. Nichols, M.B. Nichols, G.K.W. Yim, Synthesis and adren-ergic blocking effects of 2-(alkylamino)-3,4-dihydroquinazolines, Journal ofMedicinal Chemistry 23 (1980) 1261e1264.

[60] Y. Zhang, L. Jin, H. Xiang, J. Wu, D. Hu, W. Xue, S. Yang, Synthesis and anti-cancer activities of 5,6,7-trimethoxy-N-phenyl(ethyl)-4-aminoquinazolinederivatives, European Journal of Medicinal Chemistry 66 (2013) 335e344.

[61] (a) M.M. Hamed, D.A.A. El Ella, A.B. Keeton, G.A. Piazza, M. Engel,R.W. Hartmann, A.H. Abadi, Quinazoline and tetrahydropyridothieno[2,3-d]pyrimidine derivatives as irreversible EGFR tyrosine kinase inhibitors: in-fluence of the position 4 substituent, Medicinal Chemistry Communications4 (2013) 1202e1207;(b) H.R. Tsou, N. Mamuya, B.D. Johnson, M.F. Reich, B.C. Gruber, F. Ye,R. Nilakantan, R. Shen, C. Discafani, R. DeBlanc, R. Davis, F.E. Koehn,L.M. Greenberger, Y.F. Wang, A. Wissner, 6-Substituted-4-(3-bromophenylamino)quinazolines as putative irreversible inhibitors of theepidermal growth factor receptor (EGFR) and human epidermal growthfactor receptor (HER-2) tyrosine kinases with enhanced antitumor activity,Journal of Medicinal Chemistry 44 (2001) 2719e2734.

[62] T. Kimura, H. Sunaba, K. Kamata, N. Mizuno, Efficient [WO4]2�-Catalyzedchemical fixation of carbon dioxide with 2-aminobenzonitriles to quinazo-line-2,4(1H,3H)-diones, Inorganic Chemistry 51 (2012) 13001e13008.

[63] W.-J. Li, Q. Li, D.-L. Liu, M.-W. Ding, Synthesis, fungicidal activity, and sterol14a-demethylase binding interaction of 2-azolyl-3,4-dihydroquinazolineson Penicillium digitatum, Journal of Agricultural and Food Chemistry 61(2013) 1419e1426.

[64] M.K. Prashanth, H.D. Revanasiddappa, Synthesis of some new glutamine linked2,3-disubstituted quinazolinone derivatives as potent antimicrobial and anti-oxidant agents, Medicinal Chemistry Research 22 (2013) 2665e2676.

[65] J. Ma, B. Han, J. Song, J. Hu, W. Lu, D. Yang, Z. Zhang, T. Jiang, M. Hou, Efficientsynthesis of quinazoline-2,4(1H,3H)-diones from CO2 and 2-aminobenzonitriles in water without any catalyst, Green Chemistry 15(2013) 1485e1489.

[66] D. Gupta, R. Kumar, R.K. Roy, A. Sharma, I. Ali, M. Shamsuzzaman, Synthesisand biological evaluation of some new quinazolin-4(3H)ones derivatives asanticonvulsants, Medicinal Chemistry Research 22 (2013) 3282e3288.

[67] K. Arya, R. Tomar, D.S. Rawat, Greener synthesis and photo-antiproliferativeactivity of novel fluorinated benzothiazolo[2,3-b]quinazolines, MedicinalChemistry Research 23 (2014) 896e904.

[68] A.A. Mohammadi, H. Rohi, A.A. Soorki, Synthesis and in vitro antibacterialactivities of novel 2-Aryl-3(phenylamino)-2,3-dihydroquinazolin-4(1H)-onederivatives, Journal of Heterocyclic Chemistry 50 (2013) 1129e1133.

[69] D. Rambabu, G. Raja, B.Y. Sreenivas, G.P.K. Seerapu, K.L. Kumar, G.S. Deora,D. Haldar,M.V.B. Rao,M. Pal, Spiro heterocycles as potential inhibitors of SIRT1:Pd/C-mediated synthesis of novel N-indolylmethyl spiroindoline-3,2’-quina-zolines, Bioorganic & Medicinal Chemistry Letters 23 (2013) 1351e1357.

[70] O.M.O. Habib, H.M. Hassan, A. El-Mekabaty, Novel quinazolinone derivatives:synthesis and antimicrobial activity, Medicinal Chemistry Research 22(2013) 507e519.

[71] M.A. Hussein, Synthesis, anti-inflammatory, and structure antioxidant ac-tivity relationship of novel 4-quinazoline, Medicinal Chemistry Research 22(2013) 4641e4653.

[72] A. Darehkordi, J. Reentan, M. Ramezani, An efficient ultrasonic-assistedsynthesis of the thiazolo[2,3-b]quinazoline and thiazolo[3,2-a] pyrimidinederivatives, Journal of the Iranian Chemical Society 10 (2013) 385e392.

[73] M.-M. Zhang, L. Lu, Y.-J. Zhou, X.-S. Wang, Iodine-catalyzed synthesis ofpyrrolo[1,2-a]quinazoline-3a-carboxylic acid derivatives in ionic liquids,Research on Chemical Intermediates 39 (2013) 3327e3335.

[74] H.R. Safaei,M. Shekouhy, V. Shafiee,M.Davoodi, Glycerol based ionic liquidwitha boron core: a new highly efficient and reusable promoting medium for thesynthesis of quinazolinones, Journal of Molecular Liquids 180 (2013) 139e144.

[75] B. Pettersson, J. Bergman, P.H. Svensson, Synthetic studies towards 1,5-benzodiazocines, Tetrahedron 69 (2013) 2647e2654.

[76] D. Chen, Q. Chen, M. Liu, S. Dai, L. Huang, J. Yang, W. Bao, Cascade synthesis ofazoquinazolinones by Cu(I)-catalyzed C-N coupling/C-H activation/C-N for-mation reactions under O2, Tetrahedron 69 (2013) 6461e6467.

[77] Y.-C. Chen, D.-Y. Yang, Visible light-mediated synthesis of quinazolines from1,2-Dihydroquinazoline 3-Oxides, Tetrahedron 69 (2013) 10438e10444.

[78] L. Lu, M.-M. Zhang, H. Jiang, X.-S. Wang, Structurally diversified productsfrom the reactions of 2-aminobenzamides with 1,3-cyclohexanedionescatalyzed by iodine, Tetrahedron Letters 54 (2013) 757e760.





































































































































































































































[79] A. Moghimi, R.H. Khanmiri, I. Omrani, A. Shaabani, new library of 4(3H)- and4,4’(3H,3H)-quinazolinones and 2-(5-alkyl-1,2,4-oxadiazol-3-yl)quinazolin-4(3H)-one obtained from diaminoglyoxime, Tetrahedron Letters 54 (2013)3956e3959.

[80] M. Xu, K. Xu, S. Wang, Z.-J. Yao, Assembly of indolo[1,2-c]quinazolines usingZnBr2-promoted domino hydroaminationecyclization, Tetrahedron Letters54 (2013) 4675e4678.

[81] V.B. Labade, P.V. Shinde, M.S. Shingare, A facile and rapid access towards thesynthesis of 2,3-dihydroquinazolin-4(1H)-ones, Tetrahedron Letters 54(2013) 5778e5780.

[82] A.C. Nelson, E.S. Kalinowski, T.L. Jacobson, P. Grundt, Formation of tryptan-thrin compounds upon oxone-induced dimerization of indole-3-carbaldehydes, Tetrahedron Letters 54 (2013) 6804e6806.

[83] J.R. Avalani, D.S. Patel, D.K. Raval, Saccharomyces cerevisiae catalyzed one-potsynthesis of isoindolo[2,1-a]quinazoline performed under ultrasonication,Journal of Molecular Catalysis B: Enzymatic 90 (2013) 70e75.

[84] M. Desroses, M. Scobie, T. Helleday, A new concise synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives, New Journal of Chemistry 37(2013) 3595e3597.

[85] F.-L. Zhang, Y.-F. Wang, S. Chiba, Orthogonal aerobic conversion of N-benzylamidoximes to 1,2,4-oxadiazoles or quinazolinones, Organic & BiomolecularChemistry 11 (2013) 6003e6007.

[86] Z. Chen, J. Chen, M. Liu, J. Ding, W. Gao, X. Huang, H. Wu, Unexpected copper-catalyzed cascade synthesis of quinazoline derivatives, Journal of OrganicChemistry 78 (2013) 11342e11348.

[87] A. Rostami, B. Tahmasbi, H. Gholami, H. Taymorian, Supported N-pro-pylsulfamic acid on magnetic nanoparticles used as recoverable and recy-clable catalyst for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones inwater, Chinese Chemical Letters 24 (2013) 211e214.

[88] M. Kidwai, R. Chauhan, Nafion-H� catalyzed efficient one-pot synthesis oftriazolo[5,1-b]quinazolinones and triazolo[1,5-a]pyrimidines: a green strat-egy, Journal of Molecular Catalysis A: Chemical 377 (2013) 1e6.

[89] Y. Jiang, Y. Liu, S.-J. Tu, F. Shi, Enantioselective synthesis of biologicallyimportant spiro[indoline-3,2’-quinazolines] via catalytic asymmetric isatin-involved tandem reactions, Tetrahedron: Asymmetry 24 (2013) 1286e1296.

[90] M. Ghashang, S.S. Mansoor, K. Aswin, Synthesis of 2,3-dihydroquinazolin-4(1H)-ones catalyzed by succinimide-N-sulfonic acid as a mild and efficientcatalyst, Research on Chemical Intermediates (2013), http://dx.doi.org/10.1007/s11164-013-1447-y.

[91] D. Hédou, E. Deau, C. Dubouilh-Benard, M. Sanselme, A. Martinet, E. Chosson,V. Levacher, T. Besson, Microwave-assisted [3þ2] cycloaddition and SuzukieMiyaura cross-coupling for a concise access to polyaromatic scaffolds, Eu-ropean Journal of Organic Chemistry 2013 (2013) 7533e7545.

[92] S. Santra, A.K. Bagdi, A. Majee, A. Hajra, Metal nanoparticles in “on-water”organic synthesis: one-pot nano CuO catalyzed synthesis of isoindolo[2,1-a]quinazolines, RSC Advances 3 (2013) 24931e24935.

[93] A. Gharib, B.R.H. Khorasan, M. Jahangir, M. Roshani, R. Safaee, Synthesis ofbis-2,3-dihydroquinazolin-4(1H)-ones and 2,3-Dihydroquinazolin-4(1H)-ones derivatives with the aid of silica-supported preyssler nanoparticles,Organic Chemistry International 2013 (2013) 1e14.

[94] S.U. Dighe, S. Batra, Iodine-mediated electrophilic tandem cyclization of 2-alkynylbenzaldehydes with anthranilic acid leading to 1,2-dihydroisoquinoline-fused benzoxazinones, Tetrahedron 69 (2013) 9875e9885.

[95] C. Derabli, R. Boulcina, G. Kirsch, B. Carboni, A. Debache, A DMAP-catalyzedmild and efficient synthesis of 1,2-dihydroquinazolines via a one-pot three-component protocol, Tetrahedron Letters 55 (2014) 200e204.

[96] M. Rahman, A. Sarkar, M. Ghosh, A. Majee, A. Hajra, Catalytic applicationof task specific ionic liquid on the synthesis of benzoquinazolinone de-rivatives by a multicomponent reaction, Tetrahedron Letters 55 (2013)235e239.

[97] J. Wang, Y. Zong, R. Fu, Y. Niu, G. Yue, Z. Quan, X. Wang, Y. Pan, Poly(4-vinylpyridine) supported acidic ionic liquid: a novel solid catalyst for theefficient synthesis of 2,3-dihydroquinazolin-4(1H)-ones under ultrasonicirradiation, Ultrasonics Sonochemistry 21 (2014) 29e34.

[98] M. Sharif, J. Opalach, P. Langer, M. Beller, X.-F. Wu, Oxidative synthesis ofquinazolinones and benzothiadiazine 1,1-dioxides from 2-aminobenzamideand 2-aminobenzenesulfonamide with benzyl alcohols and aldehydes, RSCAdvances 4 (2014) 8e17.

[99] S.K. Panja, S. Saha, Recyclable, magnetic ionic liquid bmim[FeCl4]-catalyzed,multicomponent, solvent-free, green synthesis of quinazolines, RSC Ad-vances 3 (2013) 14495e14500.

[100] Q. Liu, H. Yang, Y. Jiang, Y. Zhao, H. Fu, General and efficient copper-catalyzedaerobic oxidative synthesis of N-fused heterocycles using amino acids as thenitrogen source, RSC Advances 3 (2013) 15636e15644.

[101] W. Ge, X. Zhu, Y. Wei, Iodine-catalyzed oxidative system for cyclization ofprimary alcohols with o-aminobenzamides to quinazolinones using DMSO asthe oxidant in dimethyl carbonate, RSC Advances 3 (2013) 10817e10822.

[102] (a) J. Carmichael, W.G. DeGraff, A.F. Gazdar, J.D. Minna, J.B. Mitchell, Evalu-ation of a tetrazolium-based semiautomated colorimetric assay: assessmentof chemosensitivity testing, Cancer Research 47 (1987) 936e942;(b) D.K. Kim, D.H. Ryu, J.Y. Lee, N. Lee, Y.W. Kim, J.S. Kim, K. Chang, G.J. Im,T.K. Kim, W.S. Choi, Synthesis and biological evaluation of novel A-ringmodified hexacyclic camptothecin analogues, Journal of Medicinal Chemistry44 (2001) 1594e1602.

[103] D.H. Fleita, R.M. Mohareb, O.K. Sakka, Antitumor and antileishmanial eval-uation of novel heterocycles derived from quinazoline scaffold: a molecularmodeling approach, Medicinal Chemistry Research 22 (2013) 2207e2221.

[104] S. Li, X. Wang, Y. He, M. Zhao, Y. Chen, M. Feng, J. Chang, H. Ning, C. Qi, Designand synthesis of novel quinazoline nitrogen mustard derivatives as potentialtherapeutic agents for cancer, European Journal of Medicinal Chemistry 67(2013) 293e301.

[105] M.F. Ahmed, M. Youns, Synthesis and biological evaluation of a novel seriesof 6,8-Dibromo-4(3H)quinazolinone derivatives as anticancer agents, Archivder Pharmazie e Chemistry in Life Sciences 346 (2013) 610e617.

[106] M.J. Hour, K.H. Lee, T.L. Chen, K.T. Lee, Y. Zhao, H.Z. Lee, Molecular modelling,synthesis, cytotoxicity and anti-tumour mechanisms of 2-aryl-6-substitutedquinazolinones as dual-targeted anti-cancer agents, British Journal of Phar-macology 169 (2013) 1574e1586.

[107] R.N. Sharma, R. Ravani, Synthesis and screening of 2-(2-(4-substitutedpiperazine-1-yl)-5-phenylthiazol-4-yl)-3-aryl quinazolinone derivatives asanticancer agents, Medicinal Chemistry Research 22 (2013) 2788e2794.

[108] D. Pathania, M. Sechi, M. Palomba, V. Sanna, F. Berrettini, A. Sias, L. Taheri,N. Neamati, Design and discovery of novel quinazolinedione-based redoxmodulators as therapies for pancreatic cancer, Biochimica et Biophysica Acta1840 (2014) 332e343.

[109] S.I. Kovalenko, I.S. Nosulenko, A.Y. Voskoboynik, G.G. Berest, L.N. Antipenko,A.N. Antipenko, A.M. Katsev, Novel N-aryl(alkaryl)-2-[(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-6-yl)thio]acetamides: synthesis, cytotoxicity,anticancer activity, compare analysis and docking, Medicinal ChemistryResearch 22 (2013) 2610e2632.

[110] R.A. Al-Salahi, A.M. Gamal-Eldeen, A.M. Alanazi, M.A. Al-Omar,M.A. Marzouk, M.M.G. Fouda, Cytotoxicity and anti-inflammatory activity ofmethylsulfanyl-triazoloquinazolines, Molecules 18 (2013) 1434e1446.

[111] S.-L. Cao, Y.Han, C.-Z. Yuan,Y.Wang, Z.-K.Xiahou, J. Liao,R.-T.Gao, B.-B.Mao, B.-L. Zhao, Z.-F. Li, X. Xu, Synthesis and antiproliferative activity of 4-substituted-piperazine-1-carbodithioate derivatives of 2,4-diaminoquinazoline, EuropeanJournal of Medicinal Chemistry 64 (2013) 401e409.

[112] A. Kamal, J.R. Tamboli, M.J. Ramaiah, S.F. Adil, S.N.C.V.L. Pushpavalli,R. Ganesh, P. Sarma, U. Bhadra, M. Pal-Bhadra, Quinazolino linked 4b-ami-dopodophyllotoxin conjugates regulate angiogenic pathway and controlbreast cancer cell proliferation, Bioorganic & Medicinal Chemistry 21 (2013)6414e6426.

[113] T.V.T. Le, J.H. Suh, N. Kim, H.-J. Park, In silico identification of poly(ADP-ribose)polymerase-1 inhibitors and their chemosensitizing effects againstcisplatin-resistant human gastric cancer cells, Bioorganic & MedicinalChemistry Letters 23 (2013) 2642e2646.

[114] M.N. Noolvi, H.M. Patel, Synthesis, method optimization, anticancer activityof 2,3,7-trisubstituted quinazoline derivatives and targeting EGFR-tyrosinekinase by rational approach, Arabian Journal of Chemistry 6 (2013) 35e48.

[115] L. Xu, W.A. Russu, Molecular docking and synthesis of novel quinazoline an-alogues as inhibitors of transcription factors NF-kB activation and their anti-cancer activities, Bioorganic & Medicinal Chemistry 21 (2013) 540e546.

[116] V. Spanó, A. Montalbano, A. Carbone, B. Parrino, G. Cirrincione, I. Castagliuolo,P. Brun, O.-G. Issinger, P. Diana, I. Primac, D. Vedaldi, A. Salvador, P. Barraja,Synthesis of a new class of Pyrrolo[3,4-h]quinazolines with antimitotic ac-tivity, European Journal of Medicinal Chemistry 74 (2014) 340e357.

[117] S. Yang, X. Li, F. Hu, Y. Li, Y. Yang, J. Yan, C. Kuang, Q. Yang, Discovery oftryptanthrin derivatives as potent inhibitors of indoleamine 2,3-dioxygenasewith therapeutic activity in Lewis Lung Cancer (LLC) tumor-bearing mice,Journal of Medicinal Chemistry 56 (2013) 8321e8331.

[118] K. Juvale, J. Gallus, M. Wiese, Investigation of quinazolines as inhibitors ofbreast cancer resistance protein (ABCG2), Bioorganic & Medicinal Chemistry21 (2013) 7858e7873.

[119] M.T. Conconi, G. Marzaro, L. Urbani, I. Zanusso, R.D. Liddo, I. Castagliuolo,P. Brun, F. Tonus, A. Ferrarese, A. Guiotto, A. Chilin, Quinazoline-based multi-tyrosine kinase inhibitors: synthesis, modeling, antitumor and anti-angiogenic properties, European Journal of Medicinal Chemistry 67 (2013)373e383.

[120] A.M. Alanazi, I.A. Al-Suwaidan, A.A.-M. Abdel-Aziz, M.A. Mohamed, A.M. El_Morsy, A.S. El-Azab, Design, synthesis and biological evaluation of somenovel substituted 2-mercapto-3-phenethylquinazolines as antitumor agents,Medicinal Chemistry Research 22 (2013) 5566e5577.

[121] J. Cai,M. Sun,X.Wu, J. Chen, P.Wang,X.Zong,M. Ji, Design andsynthesis ofnovel4-benzothiazole amino quinazolines Dasatinib derivatives as potential anti-tumor agents, European Journal of Medicinal Chemistry 63 (2013) 702e712.

[122] F.A.M. Al-Omary, G.S. Hassan, S.M. El-Messery, M.N. Nagi, E.-S.E. Habib,H.I. El-Subbagh, Nonclassical antifolates, part 3: synthesis, biological evalu-ation and molecular modeling study of some new 2-heteroarylthio-quina-zolin-4-ones, European Journal of Medicinal Chemistry 63 (2013) 33e45.

[123] X. Zhou, X. Xie, G. Liu, Quinazoline-2,4(1H,3H)-diones inhibit the growth ofmultiple human tumor cell lines, Molecular Diversity 17 (2013) 197e219.

[124] I.A. Al-Suwaidan, A.M. Alanazi, A.A.-M. Abdel-Aziz, M.A. Mohamed, A.S. El-Azab, Design, synthesis and biological evaluation of 2-mercapto-3-phenethylquinazoline bearing anilide fragments as potential antitumoragents: molecular docking study, Bioorganic & Medicinal Chemistry Letters23 (2013) 3935e3941.

[125] S.E. Abbas, F.F. Barsoum, H.H. Georgey, E.R. Mohammed, Synthesis and anti-tumor activity of certain 2,3,6-trisubstituted quinazolin-4(3H)-one de-rivatives, Bulletin of Faculty of Pharmacy Cairo University 51 (2013) 273e282.


















































http://dx.doi.org/10.1007/s11164-013-1447-y

http://dx.doi.org/10.1007/s11164-013-1447-y











































































































































































[126] K.X. Chen, S. Venkatraman, G.N. Anilkumar, Q. Zeng, C.A. Lesburg,B. Vibulbhan, F. Velazquez, T.-Y. Chan, F. Bennet, Y. Jiang, P. Pinto, Y. Huang,O. Selyutin, S. Agrawal, H.-C. Huang, C. Li, K.-C. Cheng, N.-Y. Shih,J.A. Kozlowski, S.B. Rosenblum, F.G. Njoroge, Discovery of SCH 900188: apotent hepatitis C virus NS5B polymerase inhibitor prodrug as a develop-ment candidate, ACS Medicinal Chemistry Letters (2013), http://dx.doi.org/10.1021/ml400192w.

[127] A.L. Leivers, M. Tallant, J.B. Shotwell, S. Dickerson, M.R. Leivers,O.B. McDonald, J. Gobel, K.L. Creech, S.L. Strum, A. Mathis, S. Rogers,C.B. Moore, J. Botyanszki, Discovery of selective small molecule type IIIphosphatidylinositol 4-kinase alpha (PI4KIIIa) inhibitors as anti hepatitis C(HCV) agents, Journal of Medicinal Chemistry (2013), http://dx.doi.org/10.1021/jm400781h.

[128] R. Ramamoorthy, M. Radhakrishnan, M. Borah, Antidepressant-like ef-fects of serotonin type-3 antagonist, ondansetron: an investigation inbehaviour-based rodent models, Behavioural Pharmacology 19 (2008)29e40.

[129] M. Sharma, K. Chauhan, R. Shivahare, P. Vishwakarma, M.K. Suthar,A. Sharma, S. Gupta, J.K. Saxena, J. Lal, P. Chandra, B. Kumar, P.M.S. Chauhan,Discovery of a new class of natural product-inspired quinazolinone hybrid aspotent antileishmanial agents, Journal of Medicinal Chemistry 56 (2013)4374e4392.

[130] Y. Zheng, M. Bian, X.-Q. Deng, S.-B. Wang, Z.-S. Quan, Synthesis and anti-convulsant activity evaluation of 5-Phenyl-[1,2,4]triazolo[4,3-c]quinazolin-3-amines, Archiv der Pharmazie e Chemistry in Life Sciences 346 (2013)119e126.

[131] V. Alagarsamy, G. Saravanan, Synthesis and anticonvulsant activity of novelquinazolin-4(3H)-one derived pyrazole analogs, Medicinal ChemistryResearch 22 (2013) 1711e1722.

[132] A.S. El-Azab, S.G. Abdel-Hamide, M.M. Sayed-Ahmed, G.S. Hassan, T.M. El-Hadiyah, O.A. Al-Shabanah, O.A. Al-Deeb, H.I. El-Subbagh, Novel 4(3H)-qui-nazolinone analogs: synthesis and anticonvulsant activity, MedicinalChemistry Research 22 (2013) 2815e2827.

[133] S. Malik, S.A. Khan, Design and evaluation of new hybrid pharmacophorequinazolino-tetrazoles as anticonvulsant strategy, Medicinal ChemistryResearch 23 (2014) 207e223.

[134] M.F. Zayed, H.E.A. Ahmed, A.-S.M. Omar, A.S. Abdelrahim, K. El-Adl, Design,synthesis, and biological evaluation studies of novel quinazolinone de-rivatives as anticonvulsant agents, Medicinal Chemistry Research 22 (2013)5823e5831.

[135] M.K. Prashanth, M. Madaiah, H.D. Revanasiddappa, B. Veeresh, Synthesis,anticonvulsant, antioxidant and binding interaction of novel N-substitutedmethylquinazoline-2,4(1H,3H)-dione derivatives to bovine serum albumin: astructureeactivity relationship study, Spectrochimica Acta Part A: Molecularand Biomolecular Spectroscopy 110 (2013) 324e332.

[136] A.F. Eweas, A.O.H. El-Nezhawy, A.R. Baiuomy, M.M. Awad, Design, synthesis,anti-inflammatory, analgesic screening, and molecular docking of somenovel 2-pyridyl (3H)-quinazolin-4-one derivatives, Medicinal ChemistryResearch 22 (2013) 1011e1020.

[137] G. Saravanan, V. Alagarsamy, C.R. Prakash, Synthesis, analgesic, anti-inflammatory, and in vitro antimicrobial activities of some novel quinazolin-4(3H)-one derivatives, Medicinal Chemistry Research 22 (2013) 340e350.

[138] A.A. Farag, E.M. Khalifa, N.A. Sadik, S.Y. Abbas, A.G. Al-Sehemi, Y.A. Ammar,Synthesis, characterization, and evaluation of some novel 4(3H)-quinazoli-none derivatives as anti-inflammatory and analgesic agents, MedicinalChemistry Research 22 (2013) 440e452.

[139] M.F. Zayed, M.H. Hassan, Synthesis and biological evaluation studies of novelquinazolinone derivatives as antibacterial and anti-inflammatory agents, SaudiPharmaceutical Journal (2013), http://dx.doi.org/10.1016/j.jsps.2013.03.004.

[140] M.B. Patel, U. Harikrishnan, N.N. Valand, N.R. Modi, S.K. Menon, Novelcationic quinazolin-4(3H)-one conjugated fullerene nanoparticles as anti-mycobacterial and antimicrobial agents, Archiv der Pharmazie e Chemistryin Life Sciences 346 (2013) 210e220.

[141] A.A. Al-Amiery, A.A.H. Kadhum, M. Shamel, M. Satar, Y. Khalid,A.B. Mohamad, Antioxidant and antimicrobial activities of novel quinazoli-nones, Medicinal Chemistry Research 23 (2014) 236e242.

[142] L.-P. Shi, K.-M. Jiang, J.-J. Jiang, Y. Jin, Y.-H. Tao, K. Li, X.-H. Wang, J. Lin,Synthesis and antimicrobial activity of polyhalobenzonitrile quinazolin-4(3H)-one derivatives, Bioorganic & Medicinal Chemistry Letters 23 (2013)5958e5963.

[143] X. Wang, Z. Li, J. Yin, M. He, W. Xue, Z. Chen, B.-A. Song, Synthesis andbioactivity evaluation of novel arylimines containing 3-aminoethyl-2-[(p-trifluoromethoxy)anilino]-4(3H)-quinazolinone moiety, Journal of Agricul-tural and Food Chemistry 61 (2013) 9575e9582.

[144] R. Guillon, F. Pagniez, C. Picot, D. Hédou, A. Tonnerre, E. Chosson, M. Duflos,T. Besson, C. Logé, P.L. Pape, Discovery of a novel broad-spectrum antifungalagent derived from albaconazole, ACS Medicinal Chemistry Letters 4 (2013)288e292.

[145] S.F. Vanparia, T.S. Patel, B.C. Dixit, R.B. Dixit, Synthesis and in vitro antimi-crobial activity of some newer quinazolinoneesulfonamide linked hybridheterocyclic entities derived from glycine, Medicinal Chemistry Research 22(2013) 5184e5196.

[146] A.M. Rana, K.R. Desai, S. Jauhari, Synthesis, characterization, and pharma-cological evaluation of 1-[2-(6-nitro-4-oxo-2-phenyl-4H-quinazolin-3-yl)-ethyl]3-phenyl ureas, Medicinal Chemistry Research 22 (2013) 225e233.

[147] V.M. Buha, D.N. Rana, M.T. Chhabria, K.H. Chikhalia, B.M. Mahajan,P.S. Brahmkshatriya, N.K. Shah, Synthesis, biological evaluation and QSARstudy of a series of substituted quinazolines as antimicrobial agents, Me-dicinal Chemistry Research 22 (2013) 4096e4109.

[148] N.C. Desai, H.V. Vaghani, P.N. Shihora, A new hybrid approach and in vitroantimicrobial evaluation of novel 4(3H)-quinazolinones and thiazolidinonemotifs, Journal of Fluorine Chemistry 153 (2013) 39e47.

[149] Q.-G. Ji, D. Yang, Q. Deng, Z.-Q. Ge, L.-J. Yuan, Design, synthesis, and evalu-ation of novel 1-methyl-3-substituted quinazoline-2,4-dione derivatives asantimicrobial agents, Medicinal Chemistry Research (2013), http://dx.doi.org/10.1007/s00044-013-0813-z.

[150] J. Peng, T. Lin, W. Wang, Z. Xin, T. Zhu, Q. Gu, D. Li, Antiviral alkaloids pro-duced by the mangrove-derived fungus Cladosporium sp. PJX-41, Journal ofNatural Products 76 (2013) 1133e1140.

[151] H. Luo, J. Liu, L. Jin, D. Hu, Z. Chen, S. Yang, J. Wu, B. Song, Synthesis andantiviral bioactivity of novel (1E,4E)-1-aryl-5(2-(quinazolin-4-yloxy)phenyl)-1,4-pentadien-3-one derivatives, European Journal of MedicinalChemistry 63 (2013) 662e669.

[152] J.-M.Hwang, T.Oh, T.Kaneko,A.M.Upton, S.G. Franzblau, Z.Ma, S.-N.Cho,P.Kim,Design, synthesis, and structure�activity relationship studies of tryptanthrinsas antitubercular agents, Journal of Natural Products 76 (2013) 354e367.

[153] U. Pandit, A. Dodiya, Synthesis and antitubercular activity of novel pyrazoleequinazolinone hybrid analogs, Medicinal Chemistry Research 22 (2013)3364e3371.

[154] H.K. Maurya, R. Verma, S. Alam, S. Pandey, V. Pathak, S. Sharma,K.K. Srivastava, A.S. Negi, A. Gupta, Studies on substituted benzo[h]quina-zolines, benzo[g]indazoles, pyrazoles, 2,6-diarylpyridines as anti-tubercularagents, Bioorganic & Medicinal Chemistry Letters 23 (2013) 5844e5849.

[155] G. Patel, C.E. Karver, R. Behera, P.J. Guyett, C. Sullenberger, P. Edwards,N.E. Roncal, K. Mensa-Wilmot, M.P. Pollastri, Kinase scaffold repurposing forneglected disease drug discovery: discovery of an efficacious, Lapatanib-derived lead compound for Trypanosomiasis, Journal of Medicinal Chemis-try 56 (2013) 3820e3832.

[156] B.D. Yestrepsky, Y. Xu, M.E. Breen, X. Li, W.G. Rajeswaran, J.G. Ryu,R.J. Sorenson, Y. Tsume, M.W. Wilson, W. Zhang, D. Sun, H. Sun,S.D. Larsen, Novel inhibitors of bacterial virulence: development of 5,6-dihydrobenzo[h]quinazolin-4(3H)-ones for the inhibition of group Astreptococcal streptokinase expression, Bioorganic & Medicinal Chemistry21 (2013) 1880e1897.

[157] T.-A.N. Pham, Z. Yang, Y. Fang, J. Luo, J. Lee, H. Park, Synthesis and biologicalevaluation of novel 2,4-disubstituted quinazoline analogues as GPR119 ag-onists, Bioorganic & Medicinal Chemistry 21 (2013) 1349e1356.

[158] D. Catarzi, V. Colotta, F. Varano, D. Poli, L. Squarcialupi, G. Filacchioni,K. Varani, F. Vincenzi, P.A. Borea, C. Lambertucci, G. Cristalli, Pyrazolo[1,5-c]quinazoline derivatives and their simplified analogues as adenosine receptorantagonists: synthesis, structureeaffinity relationships and molecularmodeling studies, Bioorganic & Medicinal Chemistry 21 (2013) 283e294.

[159] R. Garlapati, N. Pottabathini, V. Gurram, K.S. Kasani, R. Gundla, C. Thulluri,P.K. Machiraju, A.B. Chaudhary, U. Addepally, R. Dayam, V.R. Chunduri,B. Patro, Development of a-glucosidase inhibitors by room temperature CeCcross couplings of quinazolinones, Organic & Biomolecular Chemistry 11(2013) 4778e4791.

[160] M.M. Vasbinder, B. Aquila, M. Augustin, H. Chen, T. Cheung, D. Cook, L. Drew,B.P. Fauber, S. Glossop, M. Grondine, E. Hennessy, J. Johannes, S. Lee, P. Lyne,M. Mörtl, C. Omer, S. Palakurthi, T. Pontz, J. Read, L. Sha, M. Shen,S. Steinbacher, H. Wang, A. Wu, M. Ye, Discovery and optimization of a novelseries of potent mutant B-RafV600E selective kinase inhibitors, Journal ofMedicinal Chemistry 56 (2013) 1996e2015.

[161] B. Barlaam, J. Anderton, P. Ballard, R.H. Bradbury, L.F.A. Hennequin,D.M. Hickinson, J.G. Kettle, G. Kirk, T. Klinowska, C. Lambert-van der Brempt,C. Trigwell, J. Vincent, D. Ogilvie, Discovery of AZD8931, an equipotent,reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors, ACSMedicinal Chemistry Letters 4 (2013) 742e746.

[162] J. Wu, W. Chen, G. Xia, J. Zhang, J. Shao, B. Tan, C. Zhang, W. Yu, Q. Weng,H. Liu, M. Hu, H. Deng, Y. Hao, J. Shen, Y. Yu, Design, synthesis, and biologicalevaluation of novel conformationally constrained inhibitors targeting EGFR,ACS Medicinal Chemistry Letters 4 (2013) 974e978.

[163] J. Amin, I. Chuckowree, G.J. Tizzard, S.J. Coles, M. Wang, J.P. Bingham,J.A. Hartley, J. Spencer, Targeting epidermal growth factor receptor withferrocene-based kinase inhibitors, Organometallics 32 (2013) 509e513.

[164] L. Xi, J.-Q. Zhang, Z.-C. Liu, J.-H. Zhang, J.-F. Yan, Y. Jin, J. Lin, Novel 5-anilinoquinazoline-8-nitro derivatives as inhibitors of VEGFR-2 tyrosine ki-nase: synthesis, biological evaluation and molecular docking, Organic &Biomolecular Chemistry 11 (2013) 4367e4378.

[165] V.K. Singh, H. Sharma, S.K. Singh, L. Gangwar, Synthesis and in vitro evaluationof N-aryl pyrido-quinazolines derivatives as potent epidermal growth factorreceptor inhibitors, Chemical Biology & Drug Design 82 (2013) 119e124.

[166] Y.-Y. Xu, S.-N. Li, G.-J. Yu, Q.-H. Hu, H.-Q. Li, Discovery of novel 4-anilinoquinazoline derivatives as potent inhibitors of epidermal growthfactor receptor with antitumor activity, Bioorganic & Medicinal Chemistry 21(2013) 6084e6091.

[167] X. Zhang, R. Li, K. Qiao, Z. Ge, L. Zhang, T. Cheng, R. Li, Novel dithiocarbamicacid esters derived from 6-Aminomethyl-4-anilinoquinazolines and 6-Aminomethyl4-anilino-3-cyanoquinolines as potent EGFR inhibitors,Archiv der Pharmazie e Chemistry in Life Sciences 346 (2013) 44e52.

http://dx.doi.org/10.1021/ml400192w

http://dx.doi.org/10.1021/ml400192w

http://dx.doi.org/10.1021/jm400781h

http://dx.doi.org/10.1021/jm400781h

























































http://dx.doi.org/10.1016/j.jsps.2013.03.004













































http://dx.doi.org/10.1007/s00044-013-0813-z

http://dx.doi.org/10.1007/s00044-013-0813-z



































































































[168] Q. Zhang, Y. Diao, F. Wang, Y. Fu, F. Tang, Q. You, H. Zhou, Design and dis-covery of 4-anilinoquinazoline ureas as multikinase inhibitors targetingBRAF, VEGFR-2 and EGFR, Medicinal Chemistry Communications 4 (2013)979e986.

[169] J. Sun, D.-D. Li, J.-R. Li, F. Fang, Q.-R. Du, Y. Qian, H.-L. Zhu, Design, synthesis,biological evaluation, and molecular modeling study of 4-alkoxyquinazolinederivatives as potential VEGFR2 kinase inhibitors, Organic & BiomolecularChemistry 11 (2013) 7676e7686.

[170] S. Lü, W. Zheng, L. Ji, Q. Luo, X. Hao, X. Li, F. Wang, Synthesis, characteriza-tion, screening and docking analysis of 4-anilinoquinazoline derivatives astyrosine kinase inhibitors, European Journal of Medicinal Chemistry 61(2013) 84e94.

[171] S. Mowafy, N.A. Farag, K.A.M. Abouzid, Design, synthesis and in vitro anti-proliferative activity of 4,6-quinazolinediamines as potent EGFR-TK in-hibitors, European Journal of Medicinal Chemistry 61 (2013) 132e145.

[172] (a) R.-D. Li, X. Zhang, Q.-Y. Li, Z.-M. Ge, R.-T. Li, Novel EGFR inhibitors preparedby combination of dithiocarbamic acid esters and 4-anilinoquinazolines,Bioorganic & Medicinal Chemistry Letters 21 (2011) 3637e3640;(b) K. Wosikowski, D. Schuurhuis, K. Johnson, S.E. Bates, K.D. Paull, T.G. Myers,J.N. Weinstein, Identification of epidermal growth factor receptor and c-erbB2pathway inhibitors by correlation with gene expression patterns, Journal ofthe National Cancer Institute 89 (1997) 1505e1515;(c) R.H. Shoemaker, The NCI60 human tumour cell line anticancer drugscreen, Nature Reviews Cancer 6 (2006) 813e823.

[173] L. Zhang, C. Fan, Z. Guo, Y. Li, S. Zhao, S. Yang, J. Zhu, D. Lin, Discovery of apotent dual EGFR/HER-2 inhibitor L-2 (selatinib) for the treatment of cancer,European Journal of Medicinal Chemistry 69 (2013) 833e841.

[174] X. Zhang, T. Peng, X. Ji, J. Li, L. Tong, Z. Li, W. Yang, Y. Xu, M. Li, J. Ding,H. Jiang, H. Xie, H. Liu, Design, synthesis and biological evaluation of novel 4-Anilinoquinazolines with C-6 urea-linked side chains as inhibitors of theepidermal growth factor receptor, Bioorganic & Medicinal Chemistry 21(2013) 7988e7998.

[175] J.-R. Li, D.-D. Li, F. Fang, Q.-R. Du, L. Lin, J. Sun, Y. Qian, H.-L. Zhu, Discovery of4,6-substituted-(diaphenylamino)quinazolines as potent c-Src inhibitors,Organic & Biomolecular Chemistry 11 (2013) 8375e8386.

[176] M.L. de Castro Barbosa, L.M. Lima, R. Tesch, C.M.R. Sant’Anna, Frank Totzke,M.H.G. Kubbutat, C. Schächtele, S.A. Laufer, E.J. Barreiro, Novel 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors, Euro-pean Journal of Medicinal Chemistry 71 (2014) 1e14.

[177] M.G. Bursavich, D. Dastrup, M. Shenderovich, K.M. Yager, D.M. Cimbora,B. Williams, D.V. Kumar, Novel Mps1 kinase inhibitors: from purine topyrrolopyrimidine and quinazoline leads, Bioorganic & Medicinal ChemistryLetters 23 (2013) 6829e6833.

[178] A. Kumar, A. Ito, M. Hirohama, M. Yoshida, K.Y.J. Zhang, Identification ofquinazolinyloxy biaryl urea as a new class of SUMO activating enzyme 1inhibitors, Bioorganic & Medicinal Chemistry Letters 23 (2013) 5145e5149.

[179] M.S. Christodoulou, A. Sacchetti, V. Ronchetti, S. Caufin, A. Silvani, G. Lesma,G. Fontana, F. Minicone, M. Ventura, M. Lahtela-Kakkonen, E. Jarho, V. Zuco,N. Martinet, F. Dapiaggi, S. Pieraccini, M. Sironi, B. Riva, F. Zunino, L.D. Via,O.M. Gia, D. Passarella, Quinazolinecarboline alkaloid evodiamine as scaffoldfor targeting topoisomerase I and sirtuins, Bioorganic & Medicinal Chemistry21 (2013) 6920e6928.

[180] A.I. Sánchez, V. Martínez-Barrasa, C. Burgos, J.J. Vaquero, J. Alvarez-Builla,E. Terricabras, V. Segarra, Synthesis and evaluation of quinazoline derivativesas phosphodiesterase 7 inhibitors, Bioorganic & Medicinal Chemistry 21(2013) 2370e2378.

[181] A. Tochowicz, S. Dalziel, O. Eidam, J.D. O’Connell III, S. Griner, J.S. Finer-Moore, R.M. Stroud, Development and binding mode assessment of N-[4-[2-Propyn-1yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclo-penta[g]quinazolin-6-yl]amino]benzoyl]-L-g-glutamyl-D-glutamic acid (BGC945), a novel thymidylate synthase inhibitor that targets tumor cells, Journalof Medicinal Chemistry 56 (2013) 5446e5455.

[182] A.T. Tran, D.Wen,N.P.West, E.N. Baker,W.J. Britton, R.J. Payne, Inhibition studieson Mycobacterium tuberculosis N-acetylglucosamine-1-phosphate uridyl-transferase (GlmU), Organic & Biomolecular Chemistry 11 (2013) 8113e8126.

[183] S.M. Roopan, F.-R.N. Khan, J.S. Jin, 3-[(2-Chloroquinolin-3-yl)methyl]quina-zolin-4(3H)-ones as potential larvicidal agents, Pakistan Journal of Pharma-ceutical Sciences 26 (2013) 747e750.

[184] Y. Zhou, Q. Feng, F. Di, Q. Liu, D. Wang, Y. Chen, L. Xiong, H. Song, Y. Li, Z. Li,Synthesis and insecticidal activities of 2,3-dihydroquinazolin-4(1H)-onederivatives targeting calcium channel, Bioorganic & Medicinal Chemistry 21(2013) 4968e4975.

[185] L.M. Break, M.A. Mosselhi, N.M. Elshafai, Nucleosides 8 [18]: ribosylation offused quinazolinesdsynthesis of new [1,2,4]Triazolo[5,1-b]- and [1,2,4]Tri-azino[3,2-b]quinazoline nucleosides of fluorescence interest, Journal ofChemistry 2013 (2013) 1e11.

[186] H.R. Safaei, M. Shekouhy, S. Khademi, V. Rahmanian, M. Safaei, Diversity-oriented synthesis of quinazoline derivatives using zirconium tetrakis(do-decylsulfate) [Zr(DS)4] as a reusable lewis acid-surfactant-combined catalyst

in tap water, Journal of Industrial and Engineering Chemistry (2013), http://dx.doi.org/10.1016/j.jiec.2013.11.037.

[187] M. Tajbakhsh, R. Hosseinzadeh, P. Rezaee, M. Tajbakhsh, H3PW12O40 cata-lyzed synthesis of benzoxazine and quinazoline in aqueous media, ChineseJournal of Catalysis 35 (2014) 58e65.

[188] L. He, H. Li, H. Neumann, M. Beller, X.-F. Wu, Highly efficient four-component synthesis of 4(3H)-Quinazolinones: palladium-catalyzed car-bonylative coupling reactions, Angewantde Chemie 126 (2014) 1444e1448.

[189] H.-F. Zheng, Z.-H. Yu, W. Yuan, Z.-L. Tang, J. Clough, Y.-C. Gu, D.-Q. Shi, FeCl3-Mediated three-component cascade reaction: an effective approach to theconstruction of highly functionalized pyrrolo[1,2-c]quinazolinones, Chem-istry e A European Journal 20 (2014) 1711e1719.

[190] S.E. Kiruthika, P.T. Perumal, CuI-catalyzed coupling of gem-dibromovinylanilidesand sulfonamides: an efficient method for the synthesis of 2-Amidoindoles andindolo[1,2-a]quinazolines, Organic Letters 16 (2014) 484e487.

[191] H. Kikuchi, S. Horoiwa, R. Kasahara, N. Hariguchi, M. Matsumoto, Y. Oshima,Synthesis of febrifugine derivatives and development of an effective and safetetrahydroquinazoline-type antimalarial, European Journal of MedicinalChemistry 76 (2014) 10e19.

[192] M.L. de Castro Barbosa, L.M. Lima, R. Tesch, C.M.R. Sant’Anna, F. Totzke,M.H.G. Kubbutat, C. Schächtele, S.A. Laufer, E.J. Barreiro, Novel 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors, Euro-pean Journal of Medicinal Chemistry 71 (2014) 1e14.

[193] M. �Spulák, J. Pourová, M. Vopr�sálová, J. Miku�sek, J. Kune�s, J. Vacek, M. Ghavre,N. Gathergood, M. Pour, Bronchodilatory quinazolines and quinoxalines:synthesis and biological evaluation, European Journal of Medicinal Chemis-try 74 (2014) 65e72.

Abbreviations

MCR: Multi-component reactionCAN: Ceric ammonium nitrateMW: MicrowaveNBS: N-Bromosuccinimidedppf: 1,10-Bis(diphenylphosphino)ferroceneNMP: N-Methyl-2-pyrrolidoneNCS: N-ChlorosuccinimideTEMPO: (2,2,6,6-Tetramethylpiperidin-1-yl)oxidanylDMSO: DimethylsulfoxideDMF: N,N-DimethylformamideDCE: 1,2-DichloroetheneIPA: Isopropyl alcoholTEA: TriethanolamineTEOF: Triethyl OrthoformateRT: Room temperatureGAA: Glacial acetic acidbpy: 2,20-BipyridinePEG: Polyethylene glycolDMFDMA: N,N-Dimethylformamide dimethyl acetalDMAP: 4-DimethylaminopyridineDPP: DiketopyrrolopyrroleMTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumHCV: Hepatitis C virusTMV: Tobacco mosaic virusCMV: CytomegalovirusGABA: g-Aminobutyric acid5-FU: FluorouracilLLC: Lewis lung cancerDNA: Deoxyribonucleic acidPARP-1: Poly [ADP-ribose] polymerase 1BCRP: Breast cancer resistance proteinSAR: StructureeactivityPK: PharmacokineticsMES: Maximal electroshock seizureMRSA: Methicillin-resistant Staphylococcus aureusEGFR: Epidermal growth factor receptorDHFR: Dihydrofolate reductasePDE7: Phosphodiesterase-7TS: Thymidylate synthasecAMP: Cyclic adenosine monophosphateKSP: Kinesin spindle proteinSA: Sulfamic acidIL: Ionic liquidTBHP: tert-Butyl hydroperoxidebmim: 1-Butyl-3-methylimidazolium.


































































































http://dx.doi.org/10.1016/j.jiec.2013.11.037

http://dx.doi.org/10.1016/j.jiec.2013.11.037










































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Recent advances in the structural library of functionalized quinazoline and quinazolinone scaffolds: Synthetic approaches and multifarious applications