Design, synthesis and anticonvulsant activity evaluation of novel 4-(4-substitutedphenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-ones.

A series of novel 4-(4-substitutedphenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock test (MES) and their neurotoxicity was evaluated by the rotarod neurotoxicity test (TOX). In the MES test, compound 4-{4-[(3-fluorobenzyl)oxy]phenyl}-3-methyl-1H-1,2,4-triazol-5(4H)-one (4n) was found to possess better anticonvulsant activity and higher safety than marketed drugs Carbamazepine with an ED50 value of 25.5 mg/kg and protective index (PI) value>48.8. In addition, the potency of compound 4n against seizures induced by Pentylenetetrazole, 3-Mercaptopropionic acid, and Bicuculline suggested its broad spectrum activity, and the mechanisms of action including inhibition of voltage-gated ion channels and modulation of GABAergic activity might involve in its anticonvulsant activity.