Design, synthesis, and pharmacological evaluation of aryl oxadiazole linked 1,2,4-triazine derivatives as anticonvulsant agents

Abstract A series of new clubbed aryl oxadiazole-1,2,4-triazine derivatives (6a-l) were designed and synthesized using appropriate chemical routes. The structures were designed having the required structural elements for any compounds to be potential anticonvulsant. Preliminary (Phase I) screening of anticonvulsant activity was performed by means of maximal electroshock seizure (MES), subcutaneous pentylenetetrazole-induced seizure (scPTZ) and behavioral activity was assessed by motor impairment test and actophotometer test. The derivatives 6-((5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)-1,2,4-triazine-3(2H)-thione (6f) and 6-((5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)amino)-1,2,4-triazine-3(2H)-thione (6g) revealed significant activity against both MES and scPTZ indicating that the compounds are effective against both generalized tonic-clonic and absence seizure. The lead compound (6g) was further evaluated for quantitative (Phase II) evaluation and emerged as most effective anticonvulsant with median effective dose of 28.5 mg/kg (MES ED50), 76.6 mg/kg (scPTZ) and toxic dose (TD50) was found to be > 500 mg/kg. In the GABA estimation study results showed significantly increased GABA concentration.