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Abstract Quinazoline nucleus possessed the potent pharmacodynamic nucleus. In addition several quinazoline derivatives possess diverse biological activities Viz. Anticonvulsant, Hyponotics, Thus in the present work, we looking forward to synthesis of a series of new heterocyclic rings containing the quinazoline nucleus. Construction of the starting material began by N-alkylation of quinazolin-4(3H)-one 1 with ethyl bromoacetate in the presence of potassium carbonate in stirring dimethylformamide at room temperature yielding the desired ethyl 2-(4-oxoquinazolin-3(4H)-yl)acetate 2. Hydrazinolysis of 2 at room temperature afforded the key intermediate 2- (4-oxoquinazolin-3(4H)-yl)acetohydrazide 3. When the acetohydrazide derivative was treated with carbon disulphide in ethanol in the presence of potassium hydroxide, 3-[(5-mercapto-1,3,4-oxadiazol-2-yl)methyl] quinazolin-4(3H)-one 4 was obtained. The treatment of 4 with iodoethane, benzyl chloride, or ethyl bromoacetate under alkaline conditions provided 3-[(5-substituted sulfanyl-1,3,4-oxadiazol-2-yl) methyl]quinazolin-4(3H)-one 5, 6, and 7 respectively. On the other hand the reaction of acetohydrazide 3 with Phenyl isothiocyanate in ethanol gave the corresponding 2-[2-(4-oxoquinazolin-3(4H)-yl)acetyl]-Nphenylhydrazinecarbothioamide 8. Depending on the reaction medium, thiadiazole or oxadiazole derivatives can be formed during the cyclization reaction of the thiosemicarbazide derivative 8. Thus, stirring at 0 °C of 8 in the presence of sulfuric acid provided 3-{[5-(phenylamino)-1,3,4- thiadiazol-2-yl]methyl}quinazolin-4(3H)-one 9. However, cyclization of 8 in the presence of HgO under reflux condition gave 3-{[5- (phenylamino)-1,3,4-oxadiazol-2-yl]methyl}quinazolin-4(3H)-one 10. The thiosemicarbazide derivative 8 was then reacted with ethyl romoacetate in the presence of anhydrous sodium acetate in absolute ethanol to afford N’-(4-oxo-3-phenylthiazolidin-2-ylidene)-2-(4-oxoquinazolin- 3(4H)-yl)acetohydrazide 11 (scheme 1) . Scheme 1. Synthesis of the target compounds 4-11. The condensation of the acetohydrazide 3 with appropriate aldehyde provided the corresponding benzylidene derivatives 12, 13, and 14. On the other hand, the reaction of acetohydrazide 3 with alkene derivative diethyl ethoxymethylenemalonate in ethanol afforded 15. When acetohydrazide 3 was reacted with ethyl chloroformate leads to the corresponding ethyl-2-[1-(4-oxoquinazolin-3(4H)-yl)acetyl] hydrazine carboxylate 16, on further condensation with hydrazine hydrate in ethanol it afforded 17. The latter product was reacted with aromatic aldehyde or cyclic ketones to give the corresponding arylidene 18, and cycloalkylidene derivatives 19 and 20 respectively. Compound 17 upon treatment with carbon disulphide and potassium hydroxide in boiling ethanol, provided the oxadiazole derivative 21 which undergo facile alkylation with benzyl chloride under alkaline conditions to afford the corresponding derivative 22 (scheme 2). Scheme 2. Synthesis of the target compounds 12-22 The preparation of nitrile derivative 23 by treatment of quinazolin- 4(3H)-one with acrylonitrile in the presence of trimethylamine appeared to be a practical starting point for the elaboration into compounds 24, 25, 26, and 27. The cyclisation of compound 23 using sodium azide and ammonium chloride under reflux condition providing tetrazole derivative 24. The versatile nitrile derivative 23 was converted into acid 25 by hydrolysis using sodium hydroxide. The treatment of 25 with N aminothiourea and phosphoryl chloride afforded 26 in low yield. The methyl ester derivative 27, formed from 25 under standard conditions, treated directly with hydrazine hydrate to give 28. The hydrazide derivative 28 is a key intermediate, which give rise to a variety of compounds by condensation with p-nitrobenzaldehyde, 3-chloro-4- fluorobenzaldehyde, or acetone afforded 29, 30, and 31, respectively. Alternatively, treatment of hydrazide derivative 28 with carbon disulphide and potassium hydroxide at reflux condition for 4h gave 32. The benzyl chloride was reacted with 32 in the presence of potassium carbonate to give 33 (scheme 3) . Scheme 3. Synthesis of the target compounds 24-33 A series of novel quinazolin-4(3H)-one derivarives were synthesized by incorporating different moieties in the 3rd position of the quinazolinone nucleus and their structures were established based on spectroscopic data. The obtained compounds were evaluated for their anticonvulsant activities using Picrotoxin model. The results of this study demonstrated that, Compounds 4, 6, 11, 12, 14, 15, 18, 19, 22, 26, 29, 31, and 32 proved to be inactive, while compounds 5, 7, 10, 21, 24, and 33 significantly prolonged the onset time for convulsions . The order in prolonging the onset time for convulsions was 24 > 7 > 33 > 5 > 21 > 10. Additionally compounds 7, 10, 21, 24 and 33 successfully protected 16.67% of animals from death and 5 protect 33.33% and all significantly delayed the death latency in the remaining animals. The pharmacological results obtained in the current studies proved that incorporation of the oxadiazole moiety through a different linker in the 3rd position of the quinazolinone nucleus for example 7, 10, 21, 24, and 33 was essential for anticonvulsant activity in this series of compounds. The present active compounds, especially 5 could be useful as a template for further modifications to produce more active analogues. |