Synthesis And Anticonvulsant Evaluation Of Triazole Derivatives

In this study, eight series of triazole derivatives (T1-T7) were designed and synthesized using7-alkoxy-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]thiazine (Ⅵ) as leading compounds, based on ring-expanding/reducing, bioisosterism and dissociation of a fused ring system.All the structures of the synthesized compounds were characterized by1H-NMR, IR and MS. We use the maximal electroshock seizure test (MES) and the rotarod test to evaluate the anticonvulsant activity and neurotoxicity of these compounds, respectively. From the preliminary screens, the compounds holding promising potency were subjected to phase II trials for quantification of their anticonvulsant activity and neurotoxicity (indicated by ED50and TD50). In addition, some compounds were tested against convulsions induced by chemical substances with the aim to further investigate their anticonvulsant activity and speculating the possible mechanism of anticonvulsant activity.The pharmacological results showed that most of the target compounds showed the anticonvulsant activity in different levels in the MES screens. Among which, the percentage of compounds which were active at minimum dose of300,100and30mg/kg were34.6%,32.3%and23.8%respectively. Only9.3%of compounds prepared were found absence of anticonvulsant activity at300mg/kg. In this study, some candidate compounds with certain development value were obtained. For examp.le, compound T1g, with an EDso value of8.0mg/kg and a protective index (PI=TD50/ED50) value of15.0, showed better anticonvulsant activity and higher safety than clinical drugs carbamazepine, phenytoin sodium and valproic acid sodium; compound T4i, though showed weaker activity than carbamazepine and phenytoin sodium (better than valproic acid sodium) with an ED50value of19.7mg/kg, exhibited a very low neurotoxicity, providing this compound a big safety margin with a PI value of34.8. This value was22folds,7.7folds and5folds of that of valproic acid sodium, carbamazepine and phenytoin sodium, respectively.In addition, compounds T1g, T3f, T4i and T7h exhibited strong inhibitory activity in chemical (pentylenetetrazole,3-mercaptopropionic acid and bicuculline) induced seizures models, which further confirmed the broad-spectrum anticonvulsant activity of these compounds. Base on the known knowledge of the seizures induced by these chemical, the mechanism of anticonvulsant activity of enhancing GABAergic activity/level or modulating the GABAA receptor were suggested.In a word, a process screening novel potential anti-epilepsy drugs was stated in the paper. The structure-activity relationships of triazole derivatives as anti-epilepsy drugs were enriched and several compounds with better pharmacological properties than clinic drugs were found. This study lays the foundation for the development of new anti-epilepsy drugs.