Synthesis and Evaluation of the Anticonvulsant Activities of 4-(2-(Alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones

In this study, a novel series of 4-(2-(alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones (4a–m) was designed and synthesized. The anticonvulsant activities of these compounds were evaluated by using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. The neurotoxicity of these compounds was evaluated using the rotarod neurotoxicity test. The majority of compounds showed anti-MES activities at 100 or 300 mg/kg. Compound4gwas considered to be the most promising, based on its potency against MES- and PTZ-induced seizures with ED50values of 23.7 and 18.9 mg/kg, respectively. The TD50value of4gwas 284.0 mg/kg, which resulted in a higher protective index (PI = TD50/ED50) value than that of carbamazepine and valproate. In an ELISA test, compound4gsignificantly increased the γ-aminobutyric acid (GABA) content in mouse brain. In addition, pretreatment with thiosemicarbazide (an inhibitor of the GABA synthesizing enzyme) significantly decreased the activity of4gin the MES model, which suggests that the mechanism through which compound4gelicits its anticonvulsive action is at least in part through increasing the GABA level in the brain.Keywords:anticonvulsant;maximal electroshock;pentylenetetrazole;benzoxazole;triazolone