Design, Synthesis, and Evaluation of Anticonvulsant Activities of New Triazolopyrimidine Derivatives.

Epilepsy, a severe brain disease affecting a large population, is treated mainly by antiepileptic drugs (AEDs). However, toxicity, intolerance, and low efficiency of the available AEDs have prompted the continual attempts in the discovery of new AEDs. In this study, we discovered a skeleton of triazolopyrimidine for the development of new AEDs. The design, synthesis, anticonvulsant activity evaluation of triazolopyrimidines and , and pyrazolopyrimidines are reported. We found that most triazolopyrimidines showed anticonvulsive activity in the maximal electroshock (MES) and pentetrazol (PTZ)-induced seizure models. On the contrary, pyrazolopyrimidines showed weak or no protective effects. Among the tested derivatives, compound , holding a median effective dose (ED of 15.8 and 14.1 mg/kg against MES and PTZ-induced seizures, respectively, was found to be the most potent one. Moreover, the protection index (PI) value of was significantly higher than that of the available AEDs such as valproate, carbamazepine, and diazepam. The antiepileptic efficacy of compound was also observed in the 3-mercaptopropionic acid and bicuculline-induced seizure models. Antagonistic effects of flumazenil and 3-MP for the anticonvulsive activity of and also the radioligand-binding assay confirmed the involvement of GABA receptors, at least benzodiazepine (BZD) receptor, in the anticonvulsant activity of compound . The docking study of compounds and with GABA receptor confirmed and explained their affinity to the BZD receptors.