Synthesis And Anticonvulsantactivity Evaluation Of 4-Pbenyl-[1,2,4]Triazolo[4,3-α]Quinazolin-5(4H)-one And Its Derivatives

In this study, to begin with, the substituted aniline was reacted with carbon disulfide and aqueous sodium hydroxide to give the sodium salt of intermediates. This was then reacted with dimethyl sulfate to afford a methyl 4-substituted phenylcarbamodithioate.Next, the solution of it in ethanol was treated with methyl anthranilate in the presence of anhydrous potassium carbonate to obtain an intermediate, which upon basic hydrolysis yielded the compounds. Then, reacted with hydrazine hydrate in ethanol to furnish a 2-hydrazono-3-substituted phenyl-2,3-dihydroquinazolin-4(1H)-one. This was treated with formic acid, acetic acid, urea, carbon disulfide, sodium nitrite, diethyl oxalate, ammonia, pyruvic acid, and acetyl acetone, respectively, a series of 4-(substituted-phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones (6a-w) with triazole and other heterocyclic substituents (7-14) was synthesized. The structures of all synthesized compounds were confirmed by 1H-NMR and 13C-NMR techniques.The compounds were evaluated for their anticonvulsant activity and neurotoxicity using by maximal electroshock (MES) test (Seizures were elicited in mice using a 60 Hz alternating current of 110 V. The current was applied via corneal electrodes for 0.2 s) and rotarod neurotoxicity (TOX) tests (animals were trained to stay on an accelerating rotarod of diameter 1-inch diameter that rotates at 6 rpm for 1 min after the specific time, three chance for one mouse) by the methods described in the ADD of the National Institutes of Health (USA). Among the compounds studied, compounds 6o and 6q showed wide margins of safety with protective indices (PI) that were much higher than those of currently used drugs (PI6o> 25.5, PI6q> 26.0). Compounds 6o and 6q showed significant oral activity against MES-induced seizures in mice, with ED50 values of 88.02 mg/kg and 94.6 mg/kg, respectively. The two compounds were also found to have potent activity against seizures that were induced by pentylenetetrazole (PTZ) and bicuculline (BIC), and the mechanisms of action including enhancing GABAergic neurotransmission and modulation of GABAergic activity might involve in their anticonvulsant activity.