Quinazolines: new horizons in anticonvulsant therapy.

European Journal of Medicinal Chemistry 80 (2014) 447e501

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European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech

Mini-review

Quinazolines: New horizons in anticonvulsant therapy Vinod G. Ugale a, *, Sanjay B. Bari b a b

Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, 425405 Maharashtra, India Department of Pharmaceutical Chemistry, H.R. Patel College of Pharmacy, Shirpur, Dhule, 425405 Maharashtra, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 1 February 2014 Received in revised form 23 April 2014 Accepted 24 April 2014 Available online 28 April 2014

The search for novel anticonvulsants with more selectivity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. The potency and selectivity in the pharmacological response of quinazolines as anticonvulsant have attracted the attention of many researchers to explore this framework for its potential. It is, therefore, topic of interest to study development of new synthetic strategies and their anticonvulsant potential based on the most recent knowledge emerging from the latest research. This review reports current progress in the area of new biologically active quinazoline scaffold as potent anticonvulsant. It is a sincere attempt to compile the synthetic and design aspects of quinazoline derivatives with significant anticonvulsant action. This structural class of compound can prove to be useful for the design and development of potent anticonvulsant agents. Ó 2014 Elsevier Masson SAS. All rights reserved.

Keywords: Synthesis quinazoline Anticonvulsant MES PTZ-induced seizure

1. Introduction Epilepsy is a common neurological condition, affecting 0.5e1% of the population worldwide (45-100 million people) [1]. Epilepsy is a family of neurologic disorders, if not treated, is associated with progressively impaired cognition and function, brain damage, and other neurologic deficits. In many cases, patients with epilepsy can maintain a normal and undisturbed life because of antiepileptic drugs (AEDs), the main stay for epilepsy treatment, can provide satisfying control or total relief of seizures [2,3]. Conventional AEDs like phenobarbital, primidone, phenytoin, carbamazepine, ethosuximide and benzodiazepine are widely used but exhibit an unfavorable side effect profile and failure to adequately control seizures. There is a significant group of patients (up to 30%) who are resistant to the available antiepileptic drugs. The long established AEDs control seizures in 50% of patients developing partial seizures and in 60e70% of those developing generalized seizures [4e6]. Furthermore, there is still a need to develop new drugs with improved efficacy and tolerability for those patients who do not respond to current AEDs [7,8]. In addition to that, drugs preventing epilepsy or its progression would be an important innovation. Thus, new concepts and original ideas for developing antiepileptic drugs are urgently needed. Quinazoline (Fig. 1) is a bicyclic compound earlier known as benzo-1,3-diazine was prepared in the laboratory by Gabriel in 1903 although one of its derivative was known much earlier [9]. * Corresponding author. E-mail address: [email protected] (V.G. Ugale). http://dx.doi.org/10.1016/j.ejmech.2014.04.072 0223-5234/Ó 2014 Elsevier Masson SAS. All rights reserved.

The chemistry of quinazoline compounds has been known from centuries; however the intense search for biologically active substances in this series began only in the last few decades. Earlier research in nineteen fifties and sixties revealed effectiveness of quinazolines not only as anti-malarial but also against various diseases caused by bacteria, protozoa and virus. But the research was restricted mostly to antimicrobials. An important stage in the development of research on the biological activity of quinazoline was the discovery of considerable soporific and sedative action of 2-methyl-3-aryl-4-quinazolone derivatives. In 1968 only two derivatives were used, anticonvulsant methaqualone and diuretic quinathazone. In last 10e15 years of research for medicinal value of quinazoline scaffold has been characterized by significant advances [10]. Quinazoline nucleus can be termed as ‘Master key’ for antiepileptic therapy as it is an important scaffold of many reported anticonvulsants [11e13]. Some of the potent anticonvulsants containing quinazoline nucleus are depicted in Fig. 2. Synthesis of quinazolines with general concepts stimulated an extensive search for not only novel AEDs but also various pharmacologically active compounds. They have been reported to possess the wide spectrum of biological activities like antiinflammatory [14], antimicrobial [15], antihistaminic [16], antidiuretic [17] and anticancer [18]. The review summarizes current propensity in the quinazolines synthetic chemistry and divulges the utility of this potent pharmacophore as a rich source of new compounds having promising anticonvulsant action. The synthetic methodologies indicate the simplicity, maneuverability and

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V.G. Ugale, S.B. Bari / European Journal of Medicinal Chemistry 80 (2014) 447e501

Fig. 1. Quinazoline Nucleus.

versatility, which offer the medicinal chemist a complete range of novel derivatives. Given the advances in synthetic methodology in recent years and the continued interest in the quinazoline skeleton will ensure that this is an important area of research in heterocyclic chemistry. The high degree of protection against seizures can be positive signs for further investigation of quinazoline derivatives as anticonvulsants. This assemblage recapitulates ongoing medicinal chemistry investigations worldwide, to explore quinazolines that can be useful in the treatment of epilepsy. 2. Quinazolines: design, synthesis and anticonvulsant activity Owing to immense synthetic importance and anticonvulsant activity exhibited by quinazoline and their derivatives, efforts have been made to generate libraries of these compounds. Maria Zappala et al. synthesized a set of novel 1-aryl-6,7-methylenedioxy-3H-quinazolin4-(thi)ones (Scheme 1) and screened as anticonvulsant agents

in DBA (dilute brown non-agouti)/2 mice. Noncompetitive AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonists a prototype compounds GYKI 52466 1-(4-aminophenyl)4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (Fig. 3), a 2,3-benzodiazepine derivative, have demonstrated significant anticonvulsant and neuroprotective action, thus providing a rationale for designing potent anticonvulsant. Reported derivatives were obtained by starting from 3,4-methylenedioxy-benzonitrile (1). Compound 3 was condensed with appropriate aromatic aldehyde in presence of ptoluenesulfonic acid to yield 2-aryl-6,7-methylenedioxy-3H-quinazolin-4-ones 4(aed). Compound 3 on reaction with 4nitrobenzaldehyde afforded the 1,2-dihydro derivative 7 which on reduction in presence of Zn and ammonium chloride gave derivative 6. Condensation of nitroamide with 4-nitrobenzoyl chloride, in the presence of 4-dimethylaminopyridine, gives N-(4-nitro-benzoyl)-4,5methylenedioxy-2-nitrobenzamide (5), which on reduction in presence of Raney-Ni/ammonium formate with ring closure gave compound 6. Synthesized compounds were provided with anticonvulsant properties comparable to those of GYKI 52466 (8). The insertion of a halogen in the 4-position of the phenyl ring (4) seems crucial. It is worth noting that the anticonvulsant activity was dependent upon the kind of the halogen. To clarify the mode of action, their affinity for the quinazolinone/2,3-benzodiazepine site of the AMPA receptor complex has been assayed [19].

Fig. 2. Potent anticonvulsants containing quinazoline scaffold [11e13].


449

Scheme 1.

Fig. 3. GYKI 52466 [19].

Series of 1-substituted 1,2 dihydroimidazo[5,1-b]quinazolinediones were synthesized (Scheme 2) and nanomolar activity at the glycine site of the NMDA (N-methyl-D-aspartic acid) receptor was reported by Andras Varadi et al. Anthranilamide (9) was condensed with diethyl oxalate to obtain ethyl 4-oxo-3H-quinazoline-2carboxylate (10) which on amidation gives 2-carboxamide derivative. Compound 11 was cyclized with different aromatic and heteroaromatic aldehydes to produce imidazoquinazoline-3,9-diones. The compound 11 on reacting with trimethyl orthoacetate in the presence of sodium methoxide in methanol led to the formation of 1-methyl-1-methoxy-imidazo[5,1-b]quinazoline-3,9(1H,2H)dione. The derivative 11 on dehydration with excess phosphorus pentoxide in xylene gave the 2-cyano compound (15), which on treatment of methanolic hydrochloric acid solution afforded the 2iminoether derivative. This compound (16) was easily cyclized to compound 17 with acetaldehyde in ethanol at ambient temperature. Prolonged heating of compound 11 with trimethyl orthoformate yielded 13. The most active compounds of the series were the 4-substituted-aryl derivatives. The size of the functional group had no marked effect on the activity profile. Preliminary pharmacological testing of selected 1-aryl-imidazoquinazolinediones revealed that these compounds were highly potent antagonists with nanomolar affinity in the [3H]5,7-dichlorokynurenic acid binding assay for NMDA receptors. These compounds may act as promising scaffold for future investigations of novel NMDA receptor antagonists [20].

Adel El-Azab et al. synthesized a new series of trisubstituted4(3H)-quinazoline derivatives, evaluated for their anticonvulsant activity against MES test (maximal electroshock seizure) and chemically PTZ (pentylentetrazol), picrotoxin and strychnine induced seizures. The synthetic strategy to prepare the target compounds is depicted in Scheme 3aec. Hydroxyquinazoline 18 on treatment with ethylbromoacetate in dry acetone in the presence of potassium carbonate yielded the derivative 19. The compound 19 on reaction with hydrazine hydrate in ethanol afforded 2-[3,4dihydro-2-methyl-3-(2-methylphenyl)-4-oxoquinazolin-8-yloxy] acetic acid hydrazide (21). Ester (19) was reacted with semicarbazide and/or thiocarbohydrazide in anhydrous pyridine to obtain 22ae22b. Reaction of 19 with 2-ethanolamine in boiling anhydrous pyridine gave N-[(2-hydroxyethyl)-2-(2-methyl-3-(2methylphenyl)-4(3H)-quinazolin-8-yloxy)]acetamide (20) which on treatment with conc. H2SO4 cyclized to yield compound 23 (Scheme 3a). Acid hydrazide 21 was reacted with various anhydrides in glacial acetic acid in the presence of anhydrous sodium acetate to give the corresponding N-(substituted-1,3dioxoisoindolin-2-yl)acetamides 27ae27c (Scheme 3b). Acid hydrazide 21 was treated with carbon disulfide in ethanolic potassium hydroxide to afford potassium salt of acid hydrazide (32), and then it was alkylated with methyl iodide to give the compound 33. Cyclization of compound 32 with boiling ethanol afforded (8-(5mercapto-1,3,4-oxadiazol-2-yl)methoxy)-[2-methyl-3-(2methylphenyl)]-4(3H)-quinazolinone, which on treatment with ethanolic solution of hydrazine hydrate yielded 8-[(4-amino-5mercapto-4H-1,2,4-triazol-3-yl)methoxy-2-methyl-3-(2methylphenyl)]-4(3H)-quinazolinone (Scheme 3c). Compounds 21, 28 and 33 proved to be the most potent compounds in preliminary screening. As a result of this the most active compounds were subjected to further investigations at different doses for quantification of their anticonvulsant activity (indicated by ED50) and neurotoxicity (indicated by TD50). These compounds were exhibited potent anticonvulsant activity against PTZ-induced seizure with ED50 values of 98, 160 and 150 mg/kg, respectively. Methaqualone and sodium valproate were used as reference drugs and these compounds produced ED50 values of 200 and 300 mg/kg, respectively. Surprisingly, the ED50 values of the selected compounds were found to be smaller compared to the reference anticonvulsant drugs at molar doses. Neurotoxicity profile (TD50) of compounds 21,

450


Scheme 2.

28 and 33 also shown low neurological discrepancy. The obtained results showed that the most active compounds could be useful as a template for future design, modification and investigation to produce more active analogs as anticonvulsant [13]. Vittoria Colotta et al. synthesized new 3-hydroxyquinazoline2,4-diones bearing a trifluoromethyl group at the 7-position and different groups at position 6. They previously reported 3-hydroxy7-chloroquinazoline-2,4-dione derivatives, as antagonists at ionotropic glutamate receptors. The reported compounds were synthesized by procedure depicted in Scheme 4aeb. The 7trifluoromethyl-1,2-dihydro-3,1-benzoxazine-2,4-dione was refluxed with O-benzylhydroxylamine in ethanol to afford the 2amino-N-benzyloxy-4-trifluoromethylbenzamide. Compound 38 on cyclization with triphosgene yielded the 3-benzyloxy-7trifluoromethylquinazoline-2,4-dione which was debenzylated with HBr in glacial acetic acid to obtain the desired 3-hydroxy derivative 40e40b. Nitration of 40b afforded the corresponding 6-nitro compound 41a that was converted into the 6-amino compound 41b. In Scheme 4b the compound 43 reacted with Omethylhydroxylamine to yield the compound 44 which on cyclization with triphosgene gave derivative 45. Nitration of 45 results into 6-nitro-3-methoxy derivative which on treatment with HBr in glacial acetic acid desmethylated to give the 3-hydroxy-6nitroquinazoline-2,4-dione. Compound 51 undergoes catalytic reduction in presence of palladium to afford 50. The derivative 50 on reaction with diformylhydrazine in pyridine yield 49. The compound 50 on reaction with 2,5-diethoxytetrahydrofuran or 2,5-

dimethoxytetrahydrofuran-3-carbaldehyde in glacial acetic acid afforded 52ae52b. Glycine (Gly)/NMDA, AMPA and KA (kainic acid) receptor binding data showed that the 7-trifluoromethyl residue increased AMPA and KA receptor affinity and selectivity, with respect to the 7-chlorine atom. Among the synthesized derivatives the 6-(1,2,4-triazol-4-yl) group (compound 49) was the most significant for AMPA receptor affinity and selectivity. Derivative 49 demonstrated to be effective in decreasing neuronal damage produced by oxygen and glucose deprivation in organotypic rat hippocampal slices and also showed good anticonvulsant activity in PTZ-induced seizures. From the observed docking results it was came to know quinazoline scaffold showing a hydrogen bonding with iGluRs: Arg96, Thr91 and Pro89 at the AMPA receptor (Fig. 4A), and the homologous Arg131, Thr126 and Pro124 at the Gly/NMDA receptor (Fig. 4B). Both the 2-carbonyl and 3-hydroxy groups of compound with chloride substitution at 7th position and 40a were found to interact with the Arg131 side chain. Compound 40a (R7 ¼ CF3) shown an increased binding affinity to AMPA receptors compared to compound with chloride substitution (R7 ¼ Cl) same was opposite for the Gly/NMDA receptor. In fact, the highly polar residues located at the top of the AMPA receptor binding pocket, such as Glu13 and Tyr61, were replaced with the more hydrophobic residues Glu13 and Phe92, in the Gly/NMDA receptor (Fig. 4A and B). These studies come with the excellent conclusion that the affinity of quinazoline derivatives with these receptors depend upon the substitution at the 7th position. 6-(1,2,4-triazole) substituted derivative 49 shown the selectivity towards AMPA receptor and it


a

b

Scheme 3.

451

452


c

Scheme 3. (continued).

was justified by the following results. The NH group of compound 49 acts as a proton donor toward the backbone C]O of Pro89, while the 2-carbonyl group accepts a hydrogen bond from the backbone eNHe of Thr91 at the AMPA receptor site (Fig. 5A). Moreover, both 2-carbonyl and 3-hydroxy groups of compound 49 interact with the side chain of Arg96. The triazole ring at the R6-position accepts a hydrogen bond from the Thr174 side chain. In fact, compound 52a completely lacks interaction with Thr174, as shown in Fig. 5A. Difference between the AMPA receptor affinities of compounds 49 and 52a can be explained by these polar interactions. Fascinatingly, the 1,2,4-triazole ring of derivative 49 was directed toward Thr174 in the AMPA receptor, which was mutated to Ala206 in the Gly/ NMDA receptor (Fig. 5B). This mutation was located in one of the less conserved regions between iGluR (ionotropic glutamate receptor) and has the direct consequence of weakening the ligand receptor interactions network [21]. Janos Almasi et al. determined the protonation macroconstants of 4-(3H)-quinazolone and two 2-methyl-4-oxo-3H-alkyl-quinazoline-3-carboxylic acid derivatives (Fig. 6) by pH-potentiometry. There results interpreted that the elongation of the aliphatic carboxylic acid side-chain has significantly modified the electrondensity of the ring system and especially carboxylate functional group modifies the extent of siteesite interactions in the molecule. It has brought about intramolecular interactions presumably via Hbond formation. The macroscopic and microscopic basicity data of selected compounds were considered as predictors of pharmacokinetic behavior and proven the fact that microspeciation was a useful tool in the process of antiepileptic drug development [22]. Flavia Varano et al. reported the synthesis and AMPA, Gly/ NMDA, and KA receptor binding affinities of a new set of 1,9disubstituted-8-chloro-pyrazolo[1,5-c]quinazoline-2-carboxylates (Scheme 5aed). The 1-chloro-9-nitro-2-ethyl ester (56a) (Scheme 5a) was obtained by chlorination of the compound 55a and nitro ester (56b) was prepared through nitration of 55b. The alkaline hydrolysis of ester afforded the corresponding acids 58ae58e (Scheme 5b). Again in Scheme 5c the alkaline hydrolysis of esters gave dicarboxylic acid derivatives 60ae60i (Scheme 5c). In Scheme 5d nitration of compound 61 gave 62 which on reduction gave 63. Reaction of 63 with an excess of 2,5-dimethoxy-3tetrahydrofurancarboxaldehyde yielded the 9-(3-formylpyrrol-1yl) derivative. Finally the reaction of 63 with an excess of suitable

isocyanates gave the corresponding derivatives 64ae64m. From the binding data it was showed that, these derivatives have good affinity and selectivity for AMPA receptor. The obtained results concluded that the presence of a 1,2-dicarboxylic acid group and suitable benzo-substituents were mandatory to acquire selective AMPA receptor antagonistic action. This research also revealed that the presence of a 2-carboxybenzoylamino substituent at position-9 was important for obtaining potent KA receptor antagonists [23]. A series of novel 3-[5-substituted phenyl-1,3,4-thiadiazole-2yl]-2-styryl quinazoline-4(3H)-ones were synthesized and evaluated for anticonvulsant action by Varsha Jatav et al. In Scheme 6 the benzoxazone was synthesized by reaction with anthranilic acid in presence of acetic anhydride. Benzoxazone was reacted with substituted thiadiazole in glacial acetic acid to afford the intermediate quinazoline derivative. This compound (67) was refluxed with aromatic aldehyde in glacial acetic acid to obtain target compounds (68ae68r). Compounds were examined in the MES test and PTZ induced seizure models in mice. Rotorod method was used to assess possible neurotoxicity. Compounds with phenyl, p-chlophenyl and m-chlorophenyl substituents on thiadiazole moiety were found to exhibit good anticonvulsant activity in MES screen. When screened for neurotoxicity, compound with phenyl substituent on thiadiazole showed good anticonvulsant potential without any symptoms of neurotoxicity [24]. Methaqualone analogs were synthesized (Scheme 7aec) and evaluated for their anticonvulsant activity against electrically and chemically (PTZ, picrotoxin, and strychnine) induced seizures by Adel El-Azab et al. Starting from 3-hydroxy anthranilic acid with acetic anhydride which on subsequent reaction with o-toludine in anhydrous pyridine afforded the 8-hydroxy-2-methyl-3-(2methylphenyl)-4(3H)-quinazolinone. This quinazoline derivative on catalytic reduction with potassium carbonate in methanol gave 72. Compound 72 was reacted with various acid chlorides or phenylsulfonyl chlorides in anhydrous pyridine at room temperature to obtain 8-(substituted carbonyloxy)-4(3H)-quinazolinones 73ae73i (Scheme 7a). The reaction of 72 with various halides in acetone in the presence of potassium carbonate at room temperature afforded 74ae74e (Scheme 7b). Compound 77 on reaction with various isocyanate in ethanol gave 78ae78d. These Compounds (78ae78d) were cyclized by boiling in ethanol containing triethylamine to give 80ae80c. Cyclization of compounds 78b and 78c by using


Scheme 4.

453

454


Fig. 4. Comparison between AMPA (A) and Gly/NMDA (B) receptor surface properties at the top of the binding pocket with one of the new quinazoline-2,4-dione derivatives [21].

Fig. 5. A: Predicted binding mode of compounds 49 (in white) and 52a (in gray) into the binding pocket of the AMPA receptor. B: The R6 substituent is directed towards the less conserved region between iGluRs, where Thr174 (AMPA) e Ala206 (Gly/NMDA depicted in yellow) mutation is present [21]. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

concentrated H2SO4 yielded 79ae79b (Scheme 7c). Results of antiepileptic screening were compared with the standard drugs methaqualone and sodium valproate. In structural activity relationship it was observed that the compounds with phenylsulfonyl, aliphatic alkanoyl, or methyl fragments at position 8 possess a significant anticonvulsant activity. From the pharmacological results it was also proved a propionyl moiety at position 8 greatly increases the anticonvulsant activity when compared with the aryl moieties [25]. R.S. Misra and coworkers tested eighteen different methaqualone analogs (Fig. 7) for their anticonvulsant and monoamine oxidase inhibitory activities. Quinazolines possessing hydramide moiety were found to be more selective than their corresponding

Fig. 6. 54ae54d [22].

precursor esters for anticonvulsant activity. Replacement of the phenyl group of ester analog at Ar-moiety by 2-hydroxy-3,5dichlorophenyl group increases the anticonvulsant activity. Similarly, with the hydrazide analogs introduction of a chloro group at position 2 in the phenyl ring of the styryl moiety at position 2 of the quinazolone nucleus led to an increase in the anticonvulsant activity. It was observed that 6-chloro-3-(4-benzhydrazide)-2-(20 chlorostyryl)-4-quinazolones possess maximum anticonvulsant activity and provided 60% protection against PTZ induced seizures in mice [26]. Jakob Nilsson et al. were designed and synthesized a series of 2aryl-2,6-dihydro[1,2,4]triazolo[4,3-c]quinazoline-3,5-diones (Scheme 8aec). In Scheme 8a anthranilic acid on reacting with ethoxycarbonyl isothiocyanate gave 83ae83b followed by cyclization with acetic anhydride gave 84ae84b. Deprotection and methylation of 84ae84b yielded 86ae86b. Compound 86a reacted with 3-nitro-1H-1,2,4-triazole in I2/PPh3/EtN/toluene to give the nitro-triazole derivative, subsequent reaction of compound 87 with DIPEA gave 89ae89e. Compound 86ae86b was converted to 88ae 88b by reaction with POCl3 in pyridine. Treatment of 89ae89e with 1 equiv of mCPBA afforded triazoloquinazolinediones (90ae90e). The triazoloquinazolinedione 92 was subjected to copper-free Sonogashira coupling to afford the acetylenic quinazoline derivatives 93ae93h. Hydrogen reduction of these derivatives over palladium on charcoal yielded the desired ethylene-linked aryl derivatives 94ae94h (Scheme 8c) [27]. The 2-thioxoquinazolin4(1H)-one (84b) was previously identified as the best virtual BZDR (benzodiazepine-binding site) ligand [28] in a 3D database search employing the program Catalyst (Fig. 8). Newly synthesized compounds fit into the pharmacophore model, with NH(1) interacting


b

Scheme 5.

455

456


Scheme 6.

with A2, the 4-carbonyl oxygen interacting with H2, and the 3carbamate carbonyl oxygen interacting with H1. This pharmacophore identifies the fact that the steric repulsion in a molecule results into the non-planar conformation and disables the H1 interaction. Motivating by these results, novel derivatives were synthesized and were all found to display subnanomolar affinities. 90a (Ki ¼ 0.47 nM) was chosen as the lead structure for the exploration of various substituents in position 9. The pyridyl substituted compounds 94ce94e which inhibit BZDR binding at concentrations as low as 0.17 nM were found to be most potent from the series. The derivatives with the largest substituent in position 94f and 94g indicate a repulsive interaction with the receptor essential volumes further out in the interface region resulted into decreased affinity [27]. Daniela Catarzi et al. reported 3-hydroxy-quinazoline-2,4diones (Fig. 9) which were evaluated for their affinity at the AMPA receptor in the [3H]-CNQX {[3H]-6-cyano-7nitroquinoxaline-2,3-dione} binding assay. From the results it was revealed that the presence of a N3-nitrogen containing heterocycle at position-8 of the lead framework was an essential feature for potent and selective AMPA receptor antagonists. Moreover, the presence of potent electron-withdrawing groups, such as chlorine atom, trifluoromethyl or nitro substituents at position-7 on the fused benzo-ring positively influences potency and selectivity toward the AMPA receptor. Reported derivatives were also tested for their ability to prevent sound-induced seizures in DBA/2 mice, some of these derivatives showed good anticonvulsant properties [29].

Harish Rajak et al. carried out synthesis of novel series of semicarbazones containing 1,3,4-thiadiazole and quinazoline ring. The title compounds were prepared using the synthetic strategy depicted in Scheme 9. 3-amino-2-methylquinazolin-4(3H)-ones was reacted with ethyl chloroformate to give 97. Intermediate compound on reaction with liquid ammonia in concentrated H2SO4 undergoes cyclization to give 99, which when reacted with amine in chloroform gave 100. This compound was reacted with hydrazine hydrate in dichloromethane to produce 101, which on reaction with carbonyl compounds in ethanol gave target derivatives (102ae102r). The anticonvulsant activities of the compounds were investigated using MES and PTZ models. The rotorod test was conducted to evaluate neurotoxicity. Molecular hybridization approach was used to combine three biolabile moieties to improve their anticonvulsant activity. These new findings might be significant in the future research and development of semicarbazones containing 1,3,4-thiadiazole and/or quinazoline nucleus as novel anticonvulsants [30]. Synthesis of some 5-alkoxy-tetrazolo[1,5-a]quinazoline derivatives was carried out by Huo-Jian Wang et al. Compounds were prepared as described in Scheme 10. Compounds 2,4 dichloroquinazoline reacted with various phenols or aliphatic alcohol in dimethyl sulfoxide in the presence of sodium hydroxide to give 104ae104u, which reacted further with sodium azide in dimethyl sulfoxide to afford compounds 105ae105u. Anticonvulsant activity was evaluated by using the MES test. Most of the synthesized compounds displayed weak anticonvulsant activity at a dose of 300 mg/kg. Among all the compounds, compound with ethyl group was given significant protection against MES seizure test at a dose of 100 mg/kg [31]. Cyril Usifoh et al. synthesized acetylenic derivatives of quinazolinones and quinazolinediones. The acetylenic derivatives of the quinazolinones were synthesized as depicted in Scheme 11aec. NAlkylation of the quinazolinones was carried out with propargyl bromide in dimethylformamide in the presence of potassium carbonate to produce 107ae107g. O-alkylation was occurring as a side reaction afforded phenyl and trifluoromethyl derivatives 107a and 107b respectively. Isatoic acid anhydride undergoes ring opening with 2-propyn-1-ylamine and 2-methyl-3-butyn-2-ylamine to obtain corresponding 2-aminobenzamides followed by cyclization with triethylorthoformate yielded 110. The alkyl substituted acetylenic quinazolinediones were prepared by N-alkylation of quinazolindiones with propargyl bromide using sodium hydroxide. They evaluated them for anticonvulsant activity and possible toxicity. Most compounds displayed seizure antagonizing activity in the MES test in most cases associated with little or no acute neurotoxicity. Only few compounds exhibited significant activity with subcutaneous PTZ induced seizure test. Compound 112a was selected for quantitative evaluation based on preliminary screening. Based on the ED50 in the MES test, this compound was found to be about ten-fold less active than phenytoin or carbamazepine but about as active as mesuximide. No significant result was obtained in acute neurotoxicity study of this compound when compared with standard drugs [32]. Yang Zheng et al. was synthesized novel 5-phenyl-[1,2,4]triazolo[4,3-c]quinazolin-3-amine derivatives and screened for anticonvulsant activity. All the compounds were prepared as outlined in Scheme 12aeb. Cyclization of aromatic amide with appropriate aromatic benzaldehydes gave substituted dihydroquinazolin4(1H)-ones, which on oxidization by KMnO4 gave derivative 114. The compounds 114 on sulfurization in the presence of Lawesson’s reagent produced 2-phenylquinazoline-4(3H)-thiones. Treatment of hydrazine hydrate replace sulfur form compound 115 to afford key intermediate 116ae116q. Finally intermediates 116ae116q reacted cyanogene bromide to obtain 121ae121q. Compound 116a


Scheme 7.

457

458


Fig. 7. 81ae81r [26].

reacted with formic acid, NaNO2/HCl, acetic anhydride and carbonyl di-imidazole to get the compounds 117, 118, 119 and 120 respectively. Majority of the compounds were found to be effective in the MES screens at a dose level of 100 mg/kg. From all synthesized derivatives, the most promising activity was shown by compound 121g (ED50 value of 27.4 mg/kg). This compound was then subjected to some chemical induced seizure models; including PTZ and thiosemicarbazide (TSC) induced seizure tests. Compound 121g showed inhibition of clonic seizures at a rate of 30%, and absolute protection against the tonic seizures by TSC. It was concluded that the GABA (g-aminobutyric acid) systemmediated mechanisms might be involved in its anticonvulsant activity [33]. Synthesis and evaluation of a new series of 7-substituted-4(3H)quinazolinone for their antitumor and anticonvulsant activity was carried out by Adel El-Azab et al. Starting form 4-nitroanthranilic acid with acetic anhydride followed by treatment with o-toludine in anhydrous pyridine various quinazoline derivatives were synthesized with good yield (Scheme 13a). Aminoquinazoline derivative was reacted with various aldehydes and acyl chlorides to furnish the target compounds (Scheme 13b). Moreover the compound 124 was reacted with various anhydrides and 1,3benzoxazine-4-one in boiling glacial acetic acid in the presence of anhydrous sodium acetate to give the corresponding imide (Scheme 13c). Compounds 125, 128 and 129 showed significant anticonvulsant activity as well as lower neurotoxicity than reference drugs. The most active compounds were subjected to further investigations at different doses for quantification of their anticonvulsant activity. The selected compounds were screened for anticonvulsant potency against PTZ-induced seizure. The compounds 125, 128b, 128c, 129a, 129b, 129c displayed ED50 values 0.74, 0.31, 0.35, 0.70, 0.40 and 0.41 mmol/kg respectively. Methaqualone and valproate were used as reference drugs which showed ED50 values of 1.40 and 1.5 mmol/kg respectively. Interestingly, the ED50 values of the selected compounds were found to

be smaller compared to the reference anticonvulsant drugs at the same molar doses. The obtained results showed that certain compounds could be useful as scaffold for future design, modification and investigation to produce more active analogs [13]. Adnan Kadi et al. reported a series of 2-mercapto-3-(4chlorophenyl)-4-oxo-6-iodoquinazolines. Various phenyl substituted 6-iodomercaptoquinazolines were synthesized by reaction of 6-iodomercaptoquinazolines with appropriate chloronitrobenzene, chloro-dinitrobenzene or chloronitropyridine (Scheme 14a). N-[((3-4-chlorophenyl)-4-oxo-6-iodo-3H-quinazolin-2-yl) thioacetyl]thiosemicarbazide were reacted with hydrazine hydrate, sodium hydroxide, succinic anhydride and pthalic anhydride to furnish new quinazolines with good yield (Scheme 14b). N-[(3-4chlorophenyl)-4-oxo-6-iodo-3H-quinazolin-2-yl)thioacetyl]thiosemicarbazide afforded novel quinazolines by reaction with carbon disulfide, p-chlorobenzoyl chloride and p-chlorobenzoic acid (Scheme 14c). The anticonvulsant activities of synthesized compounds screened using the PTZ-seizure threshold test. Compounds 134, 135, 142 and 143 showed a noteworthy anticonvulsant activity (200 mg/kg dose) manifested by the absence of any seizures during the 30 min period of observation. From the obtained results it seems that these compounds may interfere with the direct stimulating effect of PTZ on the neuronal membrane. Moreover, these compounds were also showed marked CNS (central nervous system) depressant activities associated with sedation and hypnosis [34]. David Orain et al. synthesized new set of quinazolinedione sulfonamide derivatives (Scheme 15aeb) as competitive AMPA receptor antagonist with improved properties. Different quinazoline were synthesized by introduction of variety of substituents on key intermediate 161. All compounds were tested in a binding assay for the orthosteric ligand binding site of AMPA receptor using rat brain homogenates and the radioligand [3H]-CNQX. Anticonvulsant screening of diverse 6-N-heteroaromatic fragments led to the identification of a highly potent compound in vitro (156a, IC50 ¼ 14 nM), but with poor in vivo efficacy after oral dosage. By


a

b

c

Scheme 8.

459

460


Fig. 8. The proposed binding mode of triazoloquinazoline-3,5-dione in the pharmacophore model representation. H1, H2 ¼ Hydrogen bond donor sites, A2, A3 ¼ Hydrogen bond acceptor sites. L1, L2 and L3 ¼ lipophilic pockets and S1e S5 ¼ Steric repulsive ligandereceptor interactions [28].

fine tuning of the physico-chemical properties and reducing the overall polarity with 6-N-nonaromatic fragments, 156i was identified with a low ED50 of 5.5 mg/kg in an animal model of anticonvulsant activity after oral dosage. Based on analysis of the X-ray structure obtained for 1,4-substituted-imidazoles and triazoles were selected in order to potentially reach an additional interaction with Glu402. The corresponding dimethylamide 156b showed a 30fold reduced binding affinity compared to 156a indicating the importance of the NH amide or a receptor spatial constraint. Presented fact was confirmed by obtaining an X-ray structure for 156a co-crystallized with a construct of the human receptor hGluA with its predicted binding mode (Fig. 10). As observed in figure, the central skeleton of 156a formed a favorable pep stacking with Tyr450. Hydrogen bonding interactions were shown by compound 156a with residues Pro478, Thr480 and Arg485. This lead also had additional hydrogen bond with Thr686 and Glu402 (NH amide) responsible for higher affinity [35]. A novel series of 3-substituted-3H-quinazolin-4-one derivatives were synthesized by Abdel Ghany El-Helby et al. The substituted anthranilic acid was reacted with isocyanate followed by potassium hydroxide gave potassium salt of quinazolines. This potassium salt on reaction with chloroacetic acid ester resulted into desired

Fig. 9. 95ae95b [29].

compounds (Scheme 16). The newly synthesized derivatives were further evaluated for anticonvulsant activity. Compounds showed the highest anticonvulsant activity at low doses (50e100 mg/kg1), whereas at doses over 100 mg/kg1 they showed a stimulant effect on the CNS that even potentiated the effect of the convulsive agent PTZ, in mice. From the structural activity relationship it revealed that the substitution at N-3 position of 3H-quinazolin-4-one nucleus by CH3 and C6H5 increases the anticonvulsant effect while substitution by C2H5 decreases the anticonvulsant effect [36]. A new set of 5,6-dihydro-pyrazolo[1,5-c]quinazoline-2carboxylates, with different substituents (COOEt, Cl, Br, CH3 and COOH) at position-1, were synthesized by Flavia Varano et al. Compounds were synthesized as outline in Scheme 17aed. The diethyl 1,2-dicarboxylate derivatives were obtained starting from the commercially available substituted isatins, which when treated with p-toluenesulfonohydrazide yielded sulfonylhydrazones. Alkaline hydrolysis of these compound furnished the 3diazo-1,3-dihydro-indol-2-one derivatives which after reaction with excess diethyl acetylenedicarboxylate yielded the tricyclic diethyl pyrazolo[1,5-c]quinazoline-1,2-dicarboxylates. Moreover, reaction of this intermediate in alkaline medium afforded different substituted quinazolines. Different esters of quinazoline were obtained by reaction with thionyl chloride in glacial acetic acid. They investigated the effect of various substituents at specific position on Gly/NMDA receptor for affinity and selectivity. Some selected compounds were also screened for their functional antagonistic activity at both the AMPA and NMDA receptor ion channels. In particular, the 2-carboxylic acids bearing a chlorine atom at position-1, were not only potent but also highly Gly/ NMDA and AMPA selective. A molecular modeling investigation has been carried out to support the observed structure activity relationship. Molecular docking clearly shows a good hydrogen bonding between the structure of pyrazolo[1,5-c]quinazoline moiety and amino acids R131/R96, T126/T91, and P124/P89 in both the Gly/NMDA receptor and AMPA receptor (Fig. 11). An aromatic residue was present in both receptors, which can bind through pep interaction with the aromatic scaffold of quinazoline ring. Compound 180a bearing a carboxylic acid group at R1 position was effective AMPA receptor antagonist because they form electrostatic interaction between the carboxylic moiety and the NH group of Ser 142. Compound 185c containing chlorine atom at R1 position was not quite effective as AMPA receptor antagonist (Fig. 11). H-bond acceptor groups, like ester or carboxylic acid, can interact with S180 of Gly/NMDA receptor, stabilizing the antagonistereceptor complex for both 180a and 185c proves them as good lead for Gly/NMDA receptor antagonist [37]. Govindaraj Saravanan et al. designed, synthesized and screened novel quinazolinone derivatives for antiepileptic activity using MES and PTZ seizure tests. Schiff bases of quinazolines were synthesized by reacting substituted quinazoline hydrazides with appropriate aldehyde in ethanol and glacial acetic acid (Scheme 18). The hopeful activity of the compounds may be credited to the substitutions at the hydrophobic domain. Compounds containing electron donating groups such as hydroxy, dimethylamino and methoxy group at the distal aryl ring showed favorable activity. At a dose of 100 mg/kg, after 0.5 h these compounds were showed protection indicating the ability to protect from seizures at relatively lower dose. Further all selected compounds in oral route showed better activity than Phenytoin [38]. Bong-Sik Yun and coworkers identified neuroprotective compounds against excitatory neurotoxins from edible and medicinal mushrooms. Dictyoquinazols 194 (A), 195 (B) and 196 (C) (Fig. 12) have been isolated from the methanolic extract of the mushroom Dictyophora indusiata. On the basis of NMR studies, their structures have been assigned as unique quinazoline compounds, which are


461

Scheme 9.

very rare in nature. The biological activity of compounds A-C to protect neuronal cells from excitotoxicity was estimated by observing primary cultured mouse cortical neurons upon treatment of excitatory neurotoxins including glutamate, AMPA, NMDA and KA receptor. Dictyoquinazols protected primary cultured mouse cortical neurons from glutamate and NMDA induced excitotoxicities in a dose-dependent manner [39]. Helen Jackson et al. evaluated the anticonvulsant effects of 197 (3-(3-cyclopropyl-5-isoxazolyl)-6-fluoro-5-morpholino-imidazo [1,5-a]quinazoline) and 198 (3-(5-cyclopropyl-1,2,4-oxadiazol-3yl)-7-fluoro-5)-(4-methyl-1-piperazinyl)-imidazo[1,5-a]quinazoline (Fig. 13) in mice and rats. Due to their high affinity with benzodiazepine receptors they prevented the seizures induced by PTZ, bicuculline, DMCM (methyl 6,7-dimethoxy-4-ethyl-1,3carboline-3-carboxylate and 3-mercaptopropionic acid in mice. Both the compounds have promising anticonvulsant activity and side-effect profile when compared with diazepam, clonazepam and abecarnil. For the assessment of tolerance, pharmacokinetic factors should also be determined and taken into consideration following chronic drug administration. Further studies have been required to explore the anticonvulsant profile of these compounds [40].

John Francis et al. synthesized 2-phenyl-[1,2,4]triazolo[1,5-c] quinazolin-5(6H)-one (Scheme 19) tricyclic heterocycles having high affinity to the BZDR. In this investigation they identified one target (2r) 9-chloro-2-(2-fluorophenyl)[1,2,4]triazolo[ 1,5-c]quinazolin5(6H)-one with activity comparable to that of the BZDR antagonist and/or inverse agonist in vitro and in vivo. Analogs were prepared to assess the importance of the 2-substituent and ring substitution in modifying activity. Among the compounds screened, three compounds were found to be potent BZDR antagonists in rat models. The 5-carbonyl group was essential for BZDR binding. Alkylation at the 6position results into reduction of binding affinity proved that the 6proton plays a significant role in the binding. The 2-substituent was very important for achieving receptor affinity in the low nanomolar or subnanomolar range. This lead will be a new tool for research in the anticonvulsant field [41]. C. M. Gupta and co-workers previously reported a variety of 3substituted 4-quinazolones and quinazolo-4-thiones with or without substituent’s on second position. In order to produce better anticonvulsant they investigated a series of 2,3-disubstituted 4quinazolones (206ae206z), 2,3-disubstituted quinazolones (207ae207f), triazepinoquinazolones (208ae208d), and

462


Scheme 10.

triazocinoquinazolones (209ae209d) (Fig. 14). These derivatives were screened for anticonvulsant activity by using MES test in mice. The test compound 206d shown good activity when administered intraperitonially with 60% protection in MES test (LD50 ¼ 1000 mg/ kg). Compound 207a showed 50% protection in MES test (LD50 ¼ 400 mg/kg) [42]. Niteen Vaidya et al. synthesized substituted 3,4-dihydro-4oxoquinazolines or 3,4-dihydro-4-oxoazaquinazolines by utilizing methyl 3-cyano-4,5-dimethylanthranilate (Scheme 20). The starting anthranilate was synthesized from the DielseAlder adduct afforded with 2-amino-3-cyano-4,5-dimethylfuran and methyl acrylate. All compounds were evaluated in mice for the MES and PTZ seizure threshold tests for potential anticonvulsant activity. Most of the methaqualone analogs were neither active nor neurotoxic. Substitution at the 6, 7 and 8-positions markedly decreased CNS action of quinazolones, although very active benzodiazepine and quinazoline analogs have been observed. The data suggest that a broad range of CNS activity was favored by the incorporation of the additional ring nitrogen in the classical methaqualone structure. Studies on the selective anticonvulsant activity of these compounds may be fruitful to get antiepileptic drug with high potency and fewer side effects [43]. Aqeel Fatmi and coworkers synthesized a series of 4,6,7,8tetrasubstituted, 3,4-dihydroquinazolines, quinazolines, quinazolin-2-ones, 1,2,3,4-tetrahydroquinazolin-2-ones (Scheme 21aeb). 3,4-dihydroquinazoline and 1,4-benzodiazepine derivatives were obtained from o-aminoketones 7(3-acyl- or 3benzoylanthranilonitriles). Synthesis of starting o-amino ketone was carried out by the DielseAlder reaction. DielseAlder adduct was obtained with 2-amino-3-cyano-4,5-dimethylfuran and the appropriate alkyl or aryl vinyl ketone. All of the newly synthesized target compounds were evaluated in mice for anticonvulsant activity. Quantification of antiepileptic activity was done by the timed intravenous PTZ seizure threshold method. From the obtained results it was confirmed that the broad spectrum effects of the

benzodiazepines and quinazolines on the seizure process can be modified by substituted heterocyclic analogs but that future lead should have less extensive substitution. Compound 222e was an unusual compound that will helpful to design new scaffold for anticonvulsant activity. Selected compounds were also evaluated for benzodiazepine receptor binding properties and in vivo antagonist potential [44]. Flavia Varano et al. worked on the synthesis and Gly/NMDA, AMPA, and KA receptor binding affinities of a set of 5,6-dihydro-5oxo-pyrazolo[1,5-c]quinazoline-2-carboxylates, 5,6-dihydro-pyrazolo[1,5-c]quinazoline-2,5-dicarboxylates and 1,5,6,10b-tetrahydro5-oxo-pyrazolo[1,5-c]quinazoline-2-carboxylates (Scheme 22aee). The compounds (227) had shown good Gly/NMDA and/or AMPA receptor binding affinities, demonstrating that the pyrazoloquinazoline tricyclic system was an adequate alternative to the triazoloquinoxaline framework for anchoring at both receptor types. Furthermore, the inactivity of the 2,5-dicarboxylate derivatives (228) at the Gly/ NMDA and AMPA receptors due to the presence of a glycine moiety in the southern portion of the pyrazoloquinazoline framework. Finally, the receptor binding studies of compounds (229) suggested that lack of planarity in the northeastern region of the molecules shifts selectivity toward the Gly/NMDA receptor, depending on the benzofused substitutions. These preliminary findings proved to be a key for further modifications on the pyrazoloquinazoline tricyclic system to improve biological activity and selectivity [45]. W. M. Welch et al. studied that sterically crowded environment surrounding the N-3 aryl group of quinazoline derivatives (Scheme 23) provided sufficient thermal stability for atropisomers. Piriqualone a compound with quinazoline skeleton found to be an antagonist of AMPA receptors. Structural fragments anthranilic acid, o-toluidine and pyridine-1-carboxaldehyde were combined to furnish the synthesis of piriqualone. Condensation of resultant 2methyl-3-aryl-quinazolin-4-one with pyridine-2-carboxaldehydes provided the desired compounds. They separated these

a

b

c

Scheme 11.

464


a

b

Scheme 12.


a

b

c

Scheme 13.

465

466


a

b

Scheme 14.


467

c


atropisomers resulted in the identification of a lead, a compound with diethyl amino substituent on pyridyl ring that binds to the AMPA receptor with high affinity (IC50 ¼ 36 nM) and displayed potent anticonvulsant activity. To resolve the issue of poor aqueous solubility of AMPA receptor antagonists, they prepared its highly crystalline mesylate salt (180 mg/mL at pH 4.7). From this context it will came to know introduction of a basic amine side chain on the pyridyl ring produced an optimal combination of potency and aqueous solubility [46]. Vittoria Colotta et al. designed novel 7-chloro-3-hydroxy-1Hquinazoline-2,4-dione derivatives (Scheme 24aed) as AMPA and kainate (KA) receptor antagonists. Starting from lead 7-chloro-3hydroxyquinazoline-2,4-dione (249) various quinazolines were synthesized by sequence of reaction. They synthesized different derivatives bearing carboxy-containing alkyl chains on the 3hydroxy group, while various heterocyclic rings or amide moieties at the 6-position of quinazoline motif and screened for antiepileptic activity. From the receptor binding study it proves that Gly/NMDA, AMPA and high-affinity KA receptors showed significant activity with the free 3-hydroxy group of quinazolines, while introduction of some 6-heterocyclic moieties yielded AMPAselective antagonists. The most fruitful result was the finding of the 6-(2-carboxybenzoylamino)-3-hydroxy-1H-quinazolin-2,4dione (255), which possesses excellent interaction with KA receptors, as well as good selectivity. Molecular modeling study was carried out with the Gly/NMDA, AMPA, and KA receptors for rationalizing affinities of the reported derivatives. The results of

docking studies of compound 255 in the homology-built model (Fig. 15) point out the interaction of the 6-carbamoyl eCOe group with the guanidine residue of Arg508. The ortho-carboxy moiety accommodates in the protein region favorable for a negatively charged group, thus establishing a direct hydrogen bond interaction with Ser674. The quinazoline ring of 255 lies about 3.7 A below and parallel to the aromatic moiety of Tyr474, thus forming a pep stacking interaction with receptor. Moreover, it is likely that the formation of an intramolecular hydrogen bond between the carboxy group and the carbamoyl eNHe further stabilized the conformation of the compound. The amino acid Ser726 and Ser706 in GluR5 permits a deeper insertion of the quinazoline ring of 255 into the GluR5 binding pocket, thus allowing a direct interaction of the 3-OH group with the side chain of Glu426. This study proves to be useful tool for guiding the design and synthesis of new AMPA and KA receptor antagonists [47]. The synthesis and binding activity at the benzodiazepine receptor of some 2-substituted pyrazolo[1,5-c]quinazolines were reported by Vittoria Colotta et al. The synthesis of 2-arylpyrazolo[1,5c]quinazolin-5-ones was described in Scheme 25aee. 4,5dihydropyrazoles were synthesized from 1,3-diaryl-2-propenones. These compounds were cyclized to yield 2-arylpyrazolo[1,5-c]quinazolin-5-ones tricyclic derivatives. The structure activity relationships of these derivatives revealed that a proton acceptor at position 1 was not mandatory binding site of a BZDR. The binding results on the fundamental pyrazolo[1,5-c]quinazolin-5-ones shown that these derivatives have good BZDR affinity with the

468


a

b

Scheme 15.


Fig. 10. X-ray structure at 1.9 A resolution of the ligand binding domain of a GluA2 construct (extracellular domain) bound to 156a selected interactions are shown in orange [35].

469

exception of the 2-(p-substituted-phenyl) derivatives. BZDR affinity of the lead compound when compared with those of their 9-chloro analogs reveals that the 9-chloro substituent had shown decreased binding potency. A non-additive 9-substituent effect has been observed. The chemical modifications performed in the lead compound at the level of the carbonyl oxygen at position 5 shown the paramount importance of the hydrogen-bonding formation between the nitrogen at position 3 and the carbonyl oxygen at position 5 with the proton donor of the receptor site [48]. Quinazoline-2,4-diones with a sulfonamide group were synthesized by Muller et al. as a novel class of competitive AMPA receptor antagonists. The substituted anthranilic esters were reacted with phosgene to obtain isocyanates which further treated with the corresponding sulfonyl hydrazide in Tetrahydrofuran. Ring closure of the intermediate by aqueous sodium hydroxide gave target compounds (Scheme 26). These derivatives proved to be effective as they possessed high receptor affinity and significant oral in vivo activity. One of the synthesized compounds, 281aa2, showed nanomolar receptor affinity, whereas other examples of the series display oral anticonvulsant activity in animal models. Koller et al. construct the human receptor hGluA2 and successfully co-

Scheme 16.

470


a

b

Scheme 17.

crystallized it with the antagonist 281aa2. An X-ray structure with a resolution of 2.1 A was obtained and demonstrated the analogy of the binding mode of the two chemo types (Fig. 16). Compound 281aa2 was oriented such that a favorable p-stacking with Tyr450 then it forms the hydrogen bond. The sulfonamide nitrogen interacts with H3Nþ-Arg485, indicating that this nitrogen was negatively charged, which enables a strong Coulomb interaction. The ring eHNe group showing the significant hydrogen bonding interaction with carbonyl group of Pro478 which may explain the drop of activity of compound 281f. The imidazole ring forms a hydrogen bond to the side chain hydroxyl group of Thr686 and the adjacent nitro group makes water mediated contacts to Tyr405 and Thr707. The ligand binding domain of the AMPA receptor showed a

high degree of homology to that of the glycine site on the NMDA receptor [49]. B. L. Chenard and co-workers synthesized quinazolin-4-one derivatives (Scheme 27) substituted at C-2 define a new class of noncompetitive antagonists at AMPA receptors. Starting reactant 5fluoroanthranilic acid combines with acetamides in the presence of POCl3 to generate the quinazolin-4-one skeleton. After deprotonation of these compound with LDA or NaH followed by quenching with various esters yielded the desired product. Methaqualone and related structures containing only the C-2 methyl group did not block AMPA receptor function at 10 mM, but when it was replaced by enol side chain the promising results were obtained. When the fluorine atom at C-6 of quinazoline was introduced it had shown


471

c

d


the potency at 0.25 mM. The aromatic 2-cyanophenyl substitution at the enol side chain gave more potent analog than any of the previously tested pyridine analogs (0.13 mM). These derivatives effectively blocks AMPA receptor mediated responses in a manner not competitive with glutamate-site agonists. As such, it will offer the medicinal chemist a new structural skeleton to explore the novel antiepileptic agent with receptor selectivity [50]. Our research group also contributed in the search of potent anticonvulsant by synthesizing a series of 6-bromo-2-ethyl-3(substitutedbenzo[d]thiazol-2-yl)quinazolin-4(3H)-one (Scheme 28) using appropriate synthetic route and evaluated experimentally by the MES and PTZ-induced seizure methods. Benzothiazoles were synthesized by using different substituted anilines which then combined with bromo substituted 2-ethyl-4(3H)-benzoxazone in dry pyridine to yield the desired derivatives. Among the tested compounds, 3-(benzo[d]thiazol-2-yl)-6-bromo-2ethylquinazolin-4(3H)-one has shown significant activity against tonic seizure by the MES model and 6-bromo-2-ethyl-3-(6methoxybenzo[d]thiazol-2-yl)quinazolin-4(3H)-one against clonic seizure by PTZ-induced seizure model. Substitution of bromine at 6th position of quinazolines has significant contribution for increase in anticonvulsant action [51]. Quinazolinone-2-carboxaldehydes, their schiff’s base and thiosemicarbazone derivatives were synthesized by Mohsen Aly et al. Condensation of quinazolinone-2-carboxaldehydes with 4-

anisidine or 4-phenetidine in benzene afforded schiff’s bases. Quinazolinone-2-carboxaldehydes were condensed with thiosemicarbazides to obtain thiosemicarbazones. 4(3H)-quinazolinone-2-carboxaldehydethiosemicarbazones were treated with divalent metal ion in dioxane to produce corresponding complexes (Scheme 29aeb). From the presented activity data, it was found that compound 292 shown profound anticonvulsant activity. When the free amino group at the end of the thiosemicarbazone moiety of this compound was replaced by secondary amino or aminophenyl moiety the activities were dropped. The results of the present study revealed that compound 292 exhibited anticonvulsant activity in a manner which proves good lead for further investigation [52]. Praveen Kumar et al. carried out synthesis of 2-(substituted)-3[substituted]aminoquinazolin-4(3H)-one by keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant activity and neurotoxicity. Different substituted benzoxazones were synthesized by using benzoyl chloride, acetic anhydride and butyric anhydride. These intermediates were treated with hydrazine hydrate to synthesize quinazoline hydrazides which on condensation with substituted benzaldehydes or isatin yielded reported compounds (Scheme 30aeb). The 6 Hz psychomotor seizure test model was used to assess the anticonvulsant potential. The compound 302h has shown significant protection against seizures and emerged as a lead in this series.

472


Fig. 11. Binding poses of 180a and 185c with Gly/NMDA (on the left) and AMPA (on the right) receptors respectively. The side chains of some very important residues in proximity (5 A ) to the docked pyrazoloquiazoline derivatives are highlighted and labeled. Hydrogen bonding interactions are indicated (dash line) [37].


Scheme 18.

Fig. 12. Dictyoquinazols 194 (A), 195 (B) and 196 (C) [39].

473

474


Fig. 13. 197, 198 [39].

Compounds 302h, 302i and 301c were used as ligands for docking studies with six established epilepsy receptors namely GABA(A) alpha-1, GABA(A) delta, glutamate, Na/H exchanger, Na channel and T-type calcium channel receptor. 302h has exhibited good binding properties with glutamate receptor (2H-bonds), GABA (A) alpha-1 receptor (H-bond) and GABA (A) delta receptor (1H-bond). Compound 302i has proved to be significant lead for antiepileptic action. This compound exhibited good hydrogen bonding interaction with glutamate receptor (4H-bonds) and GABA (A) alpha-1 receptor (1H-bond). It also showed affinity with GABA (A) delta receptor (OH-bond). Compound 301c has showing two hydrogen bonds with Thr533 and Tyr459 residues of glutamate receptor (2Hbonds). In this compound two pharmacophores were combined to produce synergistic action with lesser toxicity. It also showed affinity with GABA (A) alpha-1 receptor (OH-bond) and GABA (A)

delta receptor (OH-bond). The docking images are shown in Fig. 17. From the docking study it will put forward that these compounds exhibited good affinity and binding properties with glutamate, GABA (A) alpha-1 and GABA (A) delta receptors [53]. R. K. Goel et al. made an attempt to design, synthesize and evaluate some novel quinazolines as anticonvulsants. The design of the title compounds was based on the biological activity predictions made by the computer software PASS (prediction of activity spectra for substances). Phenyl substituent at C-4 of quinazolines showed a better potential as compared to the other aryl substituents. These derivatives were synthesized by microwave irradiation on substituted guanidines and bezaldehyde (Scheme 31). The quinazoline having a C-2 pyrrolidine group were found to be more potent as compared to those possessing the morpholino and piperidino groups. From the tabulated data it was reveals that these compounds may be acting via increasing GABA neurotransmission either directly or indirectly. Further investigations will be helpful to divulge the exact mechanism of action [54]. Sushil Kashaw et al. synthesized and screened several new 1-(4substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3yl)-urea for anticonvulsant, CNS depressant and sedativeehypnotic activity in the mice. Benzoxazones were refluxed with substituted aryl semicarbazides to afford the target compounds (Scheme 32ae d). Anticonvulsant action was examined in the MES and PTZ induced seizure models in mice. The neurotoxicity was assessed using the rotorod method. From the tabulated data of this study it was come forward that bulkier compounds like 2-Phenyl substituted compounds possessed better CNS activity as compared to 2-ethyl substitution. Incorporation of substituted

Scheme 19.


475

Fig. 14. 2,3-disubstituted 4-quinazolones (206ae206z), 2,3-disubstituted quinazolones (207ae207f), triazepinoquinazolones (208ae208d) and triazocinoquinazolones (209aed) [41].

476


Scheme 20.

phenyl urea at third position of 4-(3H)-quinazolinone leads to the development of new chemical entities with potent CNS activity as it provides hydrogen bonding area. This study gives a hypothesis that compound with lipophilic substitution and hydrogen bonding region can be proves good lead for anticonvulsant activity [55]. Uma Kabra et al. carried out investigation of some 2-ethyl-3(substituted benzothiazole-2-yl)e[3H]-quinazolin-4-ones (Scheme 33) and evaluated them for anticonvulsant activity. The newly synthesized derivatives were screened for anticonvulsant activity by MES method. The order of potencies were different depending upon different substitutions on aromatic ring of benzothiazole, it supports the fact that these compounds act by altering the lipophilicity and thereby facilitating penetration across the blood brain barrier [56]. Varsha Jatav et al. synthesized and examined series of new 3-[5substituted phenyl-1,3,4-thiadiazole-2-yl]-2-styryl quinazoline4(3H)-ones for anticonvulsant, sedative, hypnotic and CNS depression activities. Starting from anthranilic acid benzoxazone was synthesized. This intermediate was refluxed with substituted thiadiazoles in glacial acetic acid followed by treatment of aromatic aldehydes to obtain target compounds (Scheme 34). Anticonvulsant activity was assessed by MES and PTZ induced seizure models in mice. Rotorod method was employed to determine the neurotoxicity. Out of all synthesized derivatives only 361a, 316e and 316p

showed good anticonvulsant activity with epilepsy test models [57]. Vittoria Colotta et al. reported the synthesis and Gly/NMDA, AMPA and KA receptor binding activities of some 3-hydroxy-quinazoline-2,4-dione derivatives (Scheme 35). From the binding data results it can be considered a useful skeleton to obtain selective Gly/ NMDA and AMPA receptor antagonists. In fact, introduction of suitable substituents on the benzofused moiety have led to either Gly/NMDA or AMPA selective antagonists. Furthermore it also confirmed that the introduction of chlorine atom on the benzofused moiety yielded Gly/NMDA selective antagonists, while the presence of the 6-(1,2,4-triazol-4-yl) group shifted the affinity and selectivity towards the AMPA receptor [58]. A series of thiazolo-quinazoline derivatives were designed and synthesized (Scheme 36) to meet the structural requirements essential for anticonvulsant activity (Theivendren Panneerselvam et al.). Anticonvulsant activity was determined by MES and PTZ induced seizure tests. Structure activity relationship studies indicated that anticonvulsant activity increases when electron withdrawing groups were substituted on the thiazolo quinazoline nucleus, whereas an electron-releasing group decreases the activity of title compounds. Among the series, compounds substituted by electron-withdrawing groups (nitro, fluoro, bromo and chloro) and of high lipophilic nature due to nitrophenyl amino substitution


a

b

Scheme 21.

477

478


a

b

Scheme 22.


c

d


479

480


e


exhibited good anticonvulsant action than electron-releasing methoxy, methyl, and dimethyl groups [59]. Hanan Georgey et al. synthesized novel series of 3-substituted2-(substituted-phenoxymethyl) quinazolin-4-(3H)-one derivatives (Scheme 37). A preliminary evaluation of the anticonvulsant properties of the prepared compounds has indicated that some of them exhibit moderate to significant activity, compared to a diazepam standard. 2-(substituted phenoxymethyl)-4-oxoquinazolin3(4H)-carboxamides were synthesized by reacting methyl 2-(2(un/substituted phenoxy)acetamido)benzoates with guanidine hydrochloride in n-butanol. Reaction of 329 with hydrazine hydrate afforded final compounds (331ae331c). Concerning the

Scheme 23.

substitution in position 2 of quinazolin-4-(3H)-one derivatives, compound with 2-(2,4-dichlorophenoxy) substitution shown good activity when compared. Additionally, substitution in position 3 of quinazolin-4-(3H)-one derivatives affected the biological activity. The 3-(2-chloroethyl)carbonylamino derivatives were found to be more significant than their 3-chloromethylcarbonylamino analogs [60]. A. Rajasekaran and coworkers synthesized a series of novel derivatives of 3-substituted-2-thioxoquinazolin-4(3H)-ones (Scheme 38). Anthranilic acid reacted with carbon disulfide and primary amine in presence of potassium hydroxide to give 332ae 332c. These compounds reacted with secondary amines to furnish synthesis of 333ae333j. Among the newly synthesized compound 333d displayed promising anticonvulsant activity [61]. Safinaz Abbas et al. designed novel 2,3-disubstituted quinazolinone derivatives and [1,2,4]triazino[2,3-c]quinazolinone containing the pharmacophoric elements for anticonvulsant activity. The series of the 3-N-substituted aminoquinazolinone derivatives were synthesized by the treatment of aminoquinazolinone derivative with the appropriate benzaldehyde in glacial acetic acid. Reduction of the benzylideneamino derivatives with sodium borohydride yielded 338ae338d (Scheme 39a). The ester derivatives were synthesized from the chloro intermediate by reaction with the sodium/potassium salt of the appropriate acid in N,N-dimethylformamide. Treatment of compound 339 with appropriate amine in anhydrous poyassium carbonate gave 341ae341c (Scheme 39b). Synthesized compounds were screened for their anticonvulsant activity using the PTZ and MES models. LD50 for the most active compounds was calculated. From the series most active compound was 341c having a protective dose (PD50) of 200.53 mmol/kg with high safety profile (LD50 > 3000 mg/kg). Some of the compounds were found to be equal or more active than phenytoin in MES test with lesser neurotoxicity than Phenytoin [62]. A novel class of N-substituted glycosmicine derivatives were synthesized (Scheme 40), and their anticonvulsant, antioxidant activity and interaction with BSA (bovine serum albumin) were evaluated. Titled compounds were designed by considering the hypothesis that presence of an aryl hydrophobic binding site, hydrogen bonding domain, an electron donor group and another hydrophobic-hydrophilic site controlling the pharmacokinetic


a

b

Scheme 24.

481

482


c

d


Fig. 15. Compound 255 docked into a homology model of GluR5/ATPO built from the X-ray structure of the GluR2/DNQX and GluR2/ATPO complexes [47].

a

b

c

Scheme 25.

484


d

e


properties of the anticonvulsants. Findings of this study indicated that different substitutions on aromatic ring resulted in variation in antiepileptic effect. The simple phenyl ring with fluoro substitution in para-position exhibited the most potent activity and did not exhibit neurotoxicity at highest administered dose. The substitution of a small lipophilic group like fluorine at the paraposition of the phenyl ring resulted in significant anticonvulsant action. The substitution of electron donating or electron withdrawing groups to phenylaminopropanoyl at N-terminal in glycosmicine ring played key role in the anticonvulsant activity [63]. Novel quinazolines as glycine/NMDA and/or AMPA and/or KA receptor antagonists were reported by Flavia Varano et al. [37,45]. They incorporated suitable functional groups on the pyrazolo[1,5-c] quinazoline-carboxylate framework to increase the affinity and selectivity towards NMDA receptor (Scheme 41). These substituents were a carboxylate function at position-1 and/or a chlorine atom at position-9. They evaluated synthesized compounds for their affinity at glycine/NMDA, AMPA and KA receptors. These studies led to

the identification of quinazolines as glycine/NMDA receptor antagonists [64]. 3. Recent patents granted on quinazolines as anticonvulsants This section deals with the patents granted at WIPO (World Intellectual Property Organization), USPTO (United States Patent and Trademark Office) and European Patent specification related with quinazoline motif. These patents accentuate the use of the quinazolines in seizure disorder. Floersheim et al. claimed the effectiveness of quinazolines as pharmaceuticals in the treatment of epilepsy, especially in partial seizures (simple, complex and partial evolving to secondarily generalized seizures) and generalized seizures [absence (typical and atypical), myoclonic, clonic, tonic, tonic-clonic and atonic]. Furthermore, the compounds of the invention were combined with other drugs useful for the various indications, e.g. in the case of epilepsy with other anti-epileptic drugs like barbiturates,


Scheme 26.

485

486


Fig. 16. X-ray structure at 2.1 A resolution of the ligand binding domain of hGluA2 construct bound to 288aa2. Selected interactions (distances in A) and water molecules are shown in white [49].

Scheme 27.

Scheme 28.


a

b

Scheme 29.

487

488


a

b

Scheme 30.


489

Fig. 17. Representation of interaction between (a) 302h with GABA (A) alpha-1 receptor, (b) 302h with GABA (A) delta receptor, (c) 302h with glutamate receptor, (d) 302h with Na/ H exchanger; (e) 302i with GABA (A) alpha-1 receptor, (f) 302i with GABA (A) delta receptor, (g) 302i with glutamate receptor, (h) 302i with Na/H exchanger; (i) 301c with GABA (A) alpha-1 receptor, (j) 301c with GABA (A) delta receptor, (k) 301c with glutamate receptor, (l) 301c with Na/H exchanger [53].

490


Scheme 31.

a

b

c

d

Scheme 32.


Scheme 33.

Scheme 35. Scheme 34.

491

492


Scheme 36.

Scheme 37.


493

Scheme 38.

benzodiazepines, carboxamides, hydantoins, succinimides, valproic acid and other AMPA antagonists [65] (Fig. 18). Upasani et al. disclosed the use of novel quinazolines as antagonists or positive modulators of AMPA receptors, and their use for treating or preventing neuronal loss associated with stroke, global and focal ischemia, CNS trauma, and adverse effects like myclonic seizures [66] (Fig. 19). Wilson Dean et al. provided the information that quinazolines were useful inhibitors of voltage-gated sodium channels and calcium channels. The invention also provided pharmaceutically acceptable form to treat various neurodegenerative diseases including seizure disorders. The presented invention relates to usefulness of quinazolines as inhibitors of ion channels. These compounds and pharmaceutically acceptable compositions was useful for treating or lessening the severity of a trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia [67] (Fig. 20). The US patent filed by Thompson et al. disclosed that quinazolines were effective as NMDA NR2B antagonists useful for relieving pain. This invention also described the usefulness of quinazolines in the treatment of pain, migraine, depression, anxiety, schizophrenia and stroke disorders [68] (Fig. 21). The EP patent filed by Pfizer related to novel quinazolin-4one derivatives and their pharmacological activity. Pharmaceutical compositions containing such compounds were used to

treat neurodegenerative, psychotropic, and drug and alcohol induced central and peripheral nervous system disorders [69] (Fig. 22). The invention of Chen et al. described the use of these compounds in diagnosis and treatment of anxiety, sleep, seizure disorders, overdose with benzodiazepine drugs and enhancement of memory [70] (Fig. 23). The compounds of invention of Allgeier et al. described as potent competitive AMPA receptor antagonists. They were especially effective as pharmaceuticals in the treatment of epilepsy, especially in partial seizures (simple, complex and partial evolving to secondarily generalized seizures) and generalized seizures [absence (typical and atypical), myoclonic, clonic, tonic, tonicclonic and atonic]. Intravenous formulations of these compounds were useful in status epilepticus [71] (Fig. 24). The invention related to the pharmaceutical use of quinazolines as AMPA receptor antagonists disclosed by Welch et al. These compounds were used in the treatment of neurodegenerative and CNS-trauma disorders [72] (Fig. 25). 4. Summary The presented review summarizes ongoing medicinal chemistry investigations on quinazolines in search for new anticonvulsant compounds. Here the efforts have been made to depict the abilities of a large number of synthetic quinazolines and their screening for anticonvulsant activity. Many of the compounds

494


a

b

Scheme 39.


495

Scheme 40.

Scheme 41.

presented in this review have been evaluated by the ADD (Antiepileptic drug development) program. Their anticonvulsant activity has been confirmed through in vivo screening tests, although for many compounds the precise mechanism of action is still not known. Some of the newer anticonvulsant agents of this class represent structural modifications of pre-existing compounds, while others have been developed with the specific objective of modifying targets. The most common structural elements of many active compounds are an amide bond (particularly a benzylamide group) and the presence of at least one aryl unit. New data has also confirmed that the lipophilicity of new active molecules is an important factor affecting their anticonvulsant potency. From the presented data it will reveals that quinazoline containing entities may constitute important target for pharmaceutical researches, including the possibility of being mentioned as drug candidates in clinical and preclinical studies as potent anti-epileptic drug. These new agents can be used for the design of future targets and development of new drugs. Future investigations of this scaffold could give some more encouraging results. The discovery of a number of active compounds may also ultimately help to elucidate the mechanism of action of these new anticonvulsants. The authors apologize to the researchers who, for one reason or another, have not been mentioned in this anthology.

496


Fig. 18. EP Patent No. 1,773,788 [65].

Fig. 19. EP Patent No. 1,066,039 [66].


Fig. 20. U.S. Patent No. 7,718,658 [67].

Fig. 21. U.S. Patent No. 6,380,205 [68].

497

498


Fig. 22. EP Patent No. 0,884,316 [69].

Fig. 23. U.S. Patent 6,103,731 [70].


499

Fig. 24. EP Patent 2,463,278 [71].

Fig. 25. EP Patent 0,968,194 [72].

Acknowledgment Authors are thankful to the Principal Dr. S. J. Surana, R. C. Patel Institute of Pharmaceutical. Education and Research, Shirpur (Maharashtra) for providing necessary facilities.

References [1] B. Malawska, New anticonvulsant agents, Current Topics in Medicinal Chemistry 5 (2005) 69e85. [2] G.S. Bell, J.W. Sander, The epidemiology of epilepsy: the size of the problem, Seizure: The Journal of the British Epilepsy Association 11 (Suppl. A) (2002) 306e314. [3] A.T. Sørensen, M. Kokaia, Novel approaches to epilepsy treatment, Epilepsia 54 (2013) 1e10. [4] W. Löscher, D. Schmidt, New horizons in the development of antiepileptic drugs: innovative strategies, Epilepsy Research 69 (2006) 183e272. [5] M. Bialer, Chemical properties of antiepileptic drugs (AEDs), Advanced Drug Delivery Reviews 64 (2012) 887e895. [6] H.S. White, Preclinical development of antiepileptic drugs: past, present and future directions, Epilepsia 44 (Suppl. 7) (2004) 2e8. [7] D. Schmidt, M.A. Rogawski, New strategies for the identification of drugs to prevent the development or progression of epilepsy, Epilepsy Research 50 (2002) 71e78. [8] E. Perucca, J. French, M. Bialer, Development of new antiepileptic drugs: challenges, incentives, and recent advances, The Lancet Neuro 6 (2007) 793e 804.

[9] S. Manjula, E. Bharath, B. Divya, Medicinal and biological significance of quinazoline: a highly important scaffold for drug discovery: a review, International Journal of Pharma and Bio Sciences 2 (2011) 780e809. [10] T. Selvam, P. Kumar, P. Vijayaraj, Quinazoline marketed drugsea review, Research in Pharmacy 1 (2011) 1e21. [11] A. Bhaduri, N. Khanna, M. Dhar, Potential anticonvulsants synthesis of 2, 3disubstituted-4-quinazolinones and quinazolino-4-thiones, Indian Journal of Chemistry 2 (1964) 159e166. [12] M.Z.A. Badr, H.A.H. El-Sherief, A.M. Mahmoud, Studies on synthesis of 6Bromo-2, 3-disubstituted 4-quinazolinones and their thiones, Bulletin of the Chemical Society 53 (1980) 2389e2392. [13] A.S. El-Azab, K.E. ElTahir, Design and synthesis of novel 7-aminoquinazoline derivatives: antitumor and anticonvulsant activities, Bioorganic & Medicinal Chemistry Letters 22 (2012) 1879e1885. [14] V. Alagarsamy, V.R. Solomon, M. Murugan, R. Sankaranarayanan, P. Periyasamy, R. Deepa, T.D. Anandkumar, Synthesis of 3-(2-pyridyl)-2substituted-quinazolin-4(3H)-ones as new analgesic and anti-inflammatory agents, Biomedicine & Pharmacotherapy 62 (2008) 454e461. [15] F. Al-Omary, L. Abou-Zeid, M. Nagi, el.-SE. Habib, A.A. Abdel-Aziz, A.S. El-Azab, S.G. Abdel-Hamide, M.A. Al-Omar, A.M. Al-Obaid, H.I. El-Subbagh, Bioorganic & Medicinal Chemistry 18 (2010) 2849. [16] V. Alagarsamy, V. Raja Solomon, P. Parthiban, K. Dhanabal, S. Murugesan, G. Saravanan, G. Anjana, Synthesis and pharmacological investigation of novel 4-(4-ethyl phenyl)-1-substituted-4H-[1,2,4] triazolo [4,3-a]-quinazolin-5ones as new class of H1-antihistaminic agents, Journal of Heterocyclic Chemistry 45 (2008) 709e715. [17] J. Rosenberg, F. Gustafsson, S. Galatius, P.R. Hildebrandt, Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature, Cardiovascular Drugs and Therapy 19 (2005) 301e306. [18] A.J. Barker, Quinazoline Derivatives and Their Use as Anti-cancer Agents, EP Patent 0,635,498, January 25, 2001. [19] M. Zappalà, S. Grasso, N. Micale, G. Zuccalà, F.S. Menniti, G. Ferreri, G. De Sarro, C. De Micheli, 1-Aryl-6,7-methylenedioxy-3H-quinazolin-4-ones as anticonvulsant agents, Bioorganic & Medicinal Chemistry Letters 13 (2003) 4427e 4430. [20] A. Váradi, P. Horváth, T. Kurtán, A. Mándi, G. Tóth, A. Gergely, J. Kökösi, Synthesis and configurational assignment of 1,2-dihydroimidazo [5,1b] quinazoline-3,9-diones: novel NMDA receptor antagonists, Tetrahedron 68 (2012) 10365e10371. [21] V. Colotta, O. Lenzi, D. Catarzi, F. Varano, L. Squarcialupi, C. Costagli, A. Galli, C. Ghelardini, A.M. Pugliese, G. Maraula, 3-Hydroxy-1H-quinazoline-2,4-dione derivatives as new antagonists at ionotropic glutamate receptors: molecular modeling and pharmacological studies, European Journal of Medicinal Chemistry 54 (2012) 470e482. [22] J. Almási, K. Takács-Novák, J. Kökösi, B. Noszál, Characterization of potential NMDA and cholecystokinin antagonists I. Acidebase properties of 2-methyl-4-oxo-3H-quinazoline-3-alkyl-carboxylic acids at the molecular and submolecular levels, International Journal of Pharmaceutics 180 (1999) 1e11. [23] F. Varano, D. Catarzi, V. Colotta, O. Lenzi, G. Filacchioni, A. Galli, C. Costagli, Novel AMPA and kainate receptor antagonists containing the pyrazolo [1,5] quinazoline ring system: synthesis and structure activity relationships, Bioorganic & Medicinal Chemistry 16 (2008) 2617e2626.

500


[24] V. Jatav, P. Mishra, S. Kashaw, J. Stables, Synthesis and CNS depressant activity of some novel 3-[5-substituted1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones, European Journal of Medicinal Chemistry 43 (2008) 135e141. [25] A.S. El-Azab, K.E. ElTahir, S.M. Attia, Synthesis and anticonvulsant evaluation of some novel 4 (3H)-quinazolinones, Monatshefte für Chemie-Chemical Monthly 142 (2011) 837e848. [26] R. Misra, A. Chaturvedi, N. Rao, S. Parmar, Anticonvulsant and monoamine oxidase inhibitory properties of newer chlorostrylquinazolones, Pharmacological Research Communications 11 (1979) 623e633. [27] J. Nilsson, R. Gidlöf, E.Ø. Nielsen, T. Liljefors, M. Nielsen, O. Sterner, Triazoloquinazolinediones as novel high affinity ligands for the benzodiazepine site of GABA receptors, Bioorganic & Medicinal Chemistry 19 (2011) 111e121. [28] P. Kahnberg, M.H. Howard, T. Liljefors, M. Nielsen, E.Ø. Nielsen, O. Sterner, I. Pettersson, The use of a pharmacophore model for identification of novel ligands for the benzodiazepine binding site of the GABA receptor, Journal of Molecular Graphics & Modelling 23 (2004) 253e261. [29] D. Catarzi, O. Lenzi, V. Colotta, F. Varano, D. Poli, G. Filacchioni, K. Lingenhöhl, S. Ofner, Pharmacological characterization of some selected 4,5-dihydro-4oxo-1,2,4-triazolo [1,5-a] quinoxaline-2-carboxylates and 3hydroxyquinazoline-2,4-diones as (S)-2-amino-3-(3-hydroxy-5methylisoxazol-4-yl)-propionic acid receptor antagonists, Chemical & Pharmaceutical Bulletin 58 (2010) 908e911. [30] H. Rajak, B.S. Thakur, P. Kumar, P. Parmar, P.C. Sharma, R. Veerasamy, M.D. Kharya, Synthesis and antiepileptic activity of some novel semicarbazones containing 1,3,4-thiadiazole and quinazoline ring, Acta Poloniae Pharmaceutica 69 (2012) 253e261. [31] H.J. Wang, C.X. Wei, X.Q. Deng, F.L. Li, Z.S. Quan, Synthesis and evaluation on anticonvulsant and antidepressant activities of 5-alkoxy-tetrazolo [1,5-a] quinazolines, Archives of Pharmacal Research 342 (2009) 671e675. [32] C.O. Usifoh, G.K. Scriba, Synthesis and anticonvulsant activity of acetylenic quinazolinone derivatives, Archives of Pharmacal Research 333 (2000) 261e 266. [33] Y. Zheng, M. Bian, X.Q. Deng, S.B. Wang, Z.S. Quan, Synthesis and anticonvulsant activity evaluation of 5-Phenyl-[1,2,4]triazolo[4,3-c]quinazolin-3amines, Archives of Pharmacal Research 346 (2012) 119e126. [34] A.A. Kadi, A.S. El-Azab, A.M. Alafeefy, S. Abdel-Hamide, Synthesis and biological screening of some new substituted 2-Mercapto-4-(3H)-quinazolinone analogs as anticonvulsant agents, Arizona Journal of Pharmaceutical Science 34 (2009) 135e155. [35] D. Orain, S. Ofner, M. Koller, D.A. Carcache, W. Froestl, H. Allgeier, V. Rasetti, J. Nozulak, H. Mattes, N. Soldermann, 6-Amino quinazolinedione sulfonamides as orally active competitive AMPA receptor antagonists, Bioorganic & Medicinal Chemistry Letters 22 (2012) 996e999. [36] A. El-Helby, M. Wahab, Design and synthesis of some new derivatives of 3Hquinazolin-4-one with promising anticonvulsant activity, Acta Pharmaceutica 53 (2003) 127. [37] F. Varano, D. Catarzi, V. Colotta, F.R. Calabri, O. Lenzi, G. Filacchioni, A. Galli, C. Costagli, F. Deflorian, S. Moro, 1-Substituted pyrazolo [1,5H] quinazolines as novel Gly/NMDA receptor antagonists: synthesis, biological evaluation, and molecular modeling study, Bioorganic & Medicinal Chemistry 13 (2005) 5536e5549. [38] G. Saravanan, V. Alagarsamy, C.R. Prakash, Design, synthesis and anticonvulsant activities of novel 1-(substituted/unsubstituted benzylidene)-4-(4-(6,8dibromo-2-(methyl/phenyl)-4-oxoquinazolin-3(4H)-yl)phenyl) semicarbazide derivatives, Bioorganic & Medicinal Chemistry Letters 22 (2012) 3072e3078. [39] I.-K. Lee, B.-S. Yun, G. Han, D.-H. Cho, Y.-H. Kim, I.-D. Yoo, Dictyoquinazols A, B, and C, new neuroprotective compounds from the mushroom Dictyophora indusiata, Journal of Natural Products 65 (2002) 1769e1772. [40] H.C. Jackson, H.C. Hansen, M. Kristiansen, P.D. Suzdak, H. Klitgaard, M.E. Judge, M.D. Swedberg, Anticonvulsant profile of the imidazoquinazolines NNC 140185 and NNC 14-0189 in rats and mice, European Journal of Pharmacology 308 (1996) 21e30. [41] J.E. Francis, W.D. Cash, B.S. Barbaz, P.S. Bernard, R.A. Lovell, G.C. Mazzenga, R.C. Friedmann, J.L. Hyun, A.F. Braunwalder, P.S. Loo, D.A. Bennett, Synthesis and benzodiazepine binding activity of a series of novel [1,2,4]triazolo[1,5-c] quinazoline-5(6H)-ones, Journal of Medicinal Chemistry 34 (1991) 281e290. [42] C. Gupta, A. Bhaduri, N. Khanna, Drugs acting on the central nervous system. Syntheses of substituted quinazolinones and quinazolines and triazepinotriazocinoquinazolinones, Journal of Medicinal Chemistry 11 (1968) 392e395. [43] N.A. Vaidya, C. Panos, A. Kite, W.B. Iturrian, C.D. Blanton Jr., Synthesis of 3,4dihydro-4-oxoquinazoline derivatives as potential anticonvulsants, Journal of Medicinal Chemistry 26 (1983) 1422e1425. [44] A.A. Fatmi, N.A. Vaidya, W. Iturrian, C.D. Blanton Jr., Synthesis of previously inaccessible quinazolines and 1,4-benzodiazepines as potential anticonvulsants, Journal of Medicinal Chemistry 27 (1984) 772e778. [45] F. Varano, D. Catarzi, V. Colotta, G. Filacchioni, A. Galli, C. Costagli, V. Carlà, Synthesis and biological evaluation of a new set of pyrazolo [1,5-c] quinazoline-2-carboxylates as novel excitatory amino acid antagonists, Journal of Medicinal Chemistry 45 (2002) 1035e1044. [46] W. Welch, F. Ewing, J. Huang, F. Menniti, M. Pagnozzi, K. Kelly, P. Seymour, V. Guanowsky, S. Guhan, M. Guinn, Atropisomeric quinazolin-4-one derivatives are potent noncompetitive a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor antagonists, Bioorganic & Medicinal Chemistry Letters 11 (2001) 177e181.

[47] V. Colotta, D. Catarzi, F. Varano, O. Lenzi, G. Filacchioni, C. Costagli, A. Galli, C. Ghelardini, N. Galeotti, P. Gratteri, Structural investigation of the 7chloro-3-hydroxy-1H-quinazoline-2,4-dione scaffold to obtain AMPA and kainate receptor selective antagonists. synthesis, pharmacological, and molecular modeling studies, Journal of Medicinal Chemistry 49 (2006) 6015e6026. [48] V. Colotta, D. Catarzi, F. Varano, G. Filacchioni, L. Cecchi, A. Galli, C. Costagli, Synthesis and binding activity of some pyrazolo [1, 5-c] quinazolines as tools to verify an optional binding site of a benzodiazepine receptor ligand, Journal of Medicinal Chemistry 39 (1996) 2915e2921. [49] M. Koller, K. Lingenhoehl, M. Schmutz, I.-T. Vranesic, J. Kallen, Y.P. Auberson, D.A. Carcache, H. Mattes, S. Ofner, D. Orain, Quinazolinedione sulfonamides: a novel class of competitive AMPA receptor antagonists with oral activity, Bioorganic & Medicinal Chemistry Letters 21 (2011) 3358e3361. [50] B. Chenard, F. Menniti, M. Pagnozzi, K. Shenk, F. Ewing, W. Welch, Methaqualone derivatives are potent noncompetitive AMPA receptor antagonists, Bioorganic & Medicinal Chemistry Letters 10 (2000) 1203e1205. [51] V.G. Ugale, H.M. Patel, S.G. Wadodkar, S.B. Bari, A.A. Shirkhedkar, S.J. Surana, Quinazolinoebenzothiazoles: fused pharmacophores as anticonvulsant agents, European Journal of Medicinal Chemistry 53 (2012) 107e113. [52] M.M. Aly, Y.A. Mohamed, K.A. El-Bayouki, W.M. Basyouni, S.Y. Abbas, Synthesis of some new 4-(3H)-quinazolinone-2-carboxaldehyde thiosemicarbazones and their metal complexes and a study on their anticonvulsant, analgesic, cytotoxic and antimicrobial activities part-1, European Journal of Medicinal Chemistry 45 (2010) 3365e3373. [53] P. Kumar, B. Shrivastava, S.N. Pandeya, J.P. Stables, Design, synthesis and potential 6 Hz psychomotor seizure test activity of some novel 2(substituted)-3-[substituted]aminoquinazolin-4(3H)-one, European Journal of Medicinal Chemistry 46 (2011) 1006e1018. [54] R. Goel, V. Kumar, M. Mahajan, Quinazolines revisited: search for novel anxiolytic and GABAergic agents, Bioorganic & Medicinal Chemistry Letters 15 (2005) 2145e2148. [55] S.K. Kashaw, V. Kashaw, P. Mishra, N. Jain, J. Stables, Synthesis, anticonvulsant and CNS depressant activity of some new bioactive 1-(4-substituted-phenyl)3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea, European Journal of Medicinal Chemistry 44 (2009) 4335e4343. [56] U. Kabra, C. Chopde, S. Wadodkar, Design and synthesis of new derivatives of 3H-Quinazolin-4-one as potential anticonvulsant agents, Journal of Heterocyclic Chemistry 48 (2011) 1351. [57] V. Jatav, P. Mishra, S. Kashaw, J. Stables, CNS depressant and anticonvulsant 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. [58] V. Colotta, D. Catarzi, F. Varano, F.R. Calabri, G. Filacchioni, C. Costagli, A. Galli, 3-Hydroxy-quinazoline-2,4-dione as a useful scaffold to obtain selective Gly/ NMDA and AMPA receptor antagonists, Bioorganic & Medicinal Chemistry Letters 14 (2004) 2345e2349. [59] T. Panneerselvam, P.V. Kumar, C.R. Prakash, S. Raja, Synthesis and anticonvulsant activity of 6,7,8,9-tetrahydro-5H-5-(20 -hydroxy phenyl)-2(40 -substituted benzylidine)-3-(4-nitrophenyl amino) thiazolo quinazoline derivatives, Toxicological & Environmental Chemistry 93 (2011) 643e655. [60] H. Georgey, N. Abdel-Gawad, S. Abbas, Synthesis and anticonvulsant activity of some quinazolin-4-(3H)-one derivatives, Molecules 13 (2008) 2557e2569. [61] A. Rajasekaran, V. Rajamanickam, S. Darlinquine, Synthesis of some new thioxoquinazolinone derivatives and a study on their anticonvulsant and antimicrobial activities, European Review for Medical and Pharmacological Sciences 17 (2013) 95e104. [62] S.-S. Abbas, F.M. Awadallah, N.A. Ibrahim, E.G. Said, G. Kamel, Design and synthesis of some 3-Substituted-2-[(2,4-dichlorophenoxy)-methyl] quinazolin-4(3H)-one derivatives as potential anticonvulsant agents, Chemical & Pharmaceutical Bulletin 61 (2012) 679e687. [63] M. Prashanth, M. Madaiah, H. Revanasiddappa, B. Veeresh, Synthesis, anticonvulsant, antioxidant and binding interaction of novel N-substituted methylquinazoline-2,4 (1H,3H)-dione derivatives to bovine serum albumin: a structure-activity relationship study, Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy 110 (2013) 324e333. [64] F. Varano, D. Catarzi, V. Colotta, D. Poli, G. Filacchioni, A. Galli, C. Costagli, Synthesis and biological evaluation of a new set of pyrazolo [1,5-c] quinazolines as glycine/N-methyl-D-aspartic acid receptor antagonists, Chemical & Pharmaceutical Bulletin 57 (2009) 826e829. [65] P. Floersheim, H. Allgeier, W. Froestl, M. Koller, H. Mattes, J. Nozulak, S. Ofner, D. Orain, V. Rasetti, J. Renaud, Quinazoline Derivatives, EP Patent 1,773,788, November 14, 2012. [66] R. Upasani, X. Cai, N.C. Lan, Y. Wang, G. Field, D.B. Fick, Substituted Quinazolines and Analogs and the Use Thereof, EP Patent 1,066,039, January 10, 2001. [67] D. Wilson, L. Fanning, P. Krenitsky, J. Boger, Quinazolines Useful as Modulators of Ion Channels, U.S. Patent 7,718,658, May 18, 2010. [68] W. Thompson, 2-Cyclohexyl Quinazoline NMDA/NR2B Antagonists, U.S. Patent 6,380,205, April 30, 2002. [69] B.L. Chenard, W.M. Welch, Quinazoline-4-one AMPA Antagonists, EP Patent 0,884,316, September 30, 2002. [70] P. Chen, A. Hutchison, G. Cai, Imidazol [1,5-c] Quinazolines; a New Class of GABA Brain Receptor, U.S. Patent 6,103,731, August 15, 2000.

V.G. Ugale, S.B. Bari / European Journal of Medicinal Chemistry 80 (2014) 447e501 [71] H. Allgeier, J. Nozulak, D. Orain, J. Renaud, Y. Auberson, D. Carcache, P. Floersheim, C. Guibourdenche, W. Froestl, J. Kallen, 1H-Quinazoline-2,4diones and Their Use as AMPA-receptor Ligands, EP Patent 2,463,278, January 13, 2012. [72] W.M. Welch, K.M. Devries, Atropisomers of 3-aryl-4(3H)-quinazolinones and Their Use as AMPA-receptor Antagonists, EP Patent 0,968,194, May 26, 2004.

Abbreviations AED: antiepileptic drugs DBA: dilute brown non-agouti AMPA: a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid NMDA: N-methyl-D-aspartic acid MES: maximal electroshock seizure PTZ: pentylentetrazol

KA: kainic acid Gly: glycine iGluRs: ionotropic glutamate receptor BZDR: benzodiazepine-binding site receptor [3H]-CNQX: {[3H]-6-cyano-7-nitroquinoxaline-2,3-dione} TSC: thiosemicarbazide GABA: g-aminobutyric acid CNS: central nervous system DMCM: methyl 6,7-dimethoxy-4-ethyl-13-carboline-3-carboxylate PASS: prediction of activity spectra for substances BSA: bovine serum albumin ADD: antiepileptic drug development CNQX: 6-cyano-7-nitroquinoxaline-2,3-dione DNQX: 6,7-dinitroquinoxaline-2,3-dione ATPO: 3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl] propionic acid

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