Design,Synthesis And Activity Of Antiepileptic 1,2,4-triazole-pyrimidine Compounds

Epilepsy has caused serious harm to the patient’s body and mind.Clinical drugs have some shortcomings such as low activity,high neurotoxicity and unclear mechanism of action.And about 30%of patients still develop resistance.Therefore,it is of great significance to develop a new antiepileptic drug with high activity,low neurotoxicity and clear mechanism of action.In our previous study,it was found that the antiepileptic activity of 1,2,4-triazolepyrimidine compounds in vivo was significantly correlated with the planarity and lipid solubility of the molecules.In order to develop 1,2,4-triazolopyrimidine compounds with higher activity and clearer mechanisms of action,We have designed and synthesized two novel 1,2,4-triazole-pyrimidine derivatives.We also studied antiepileptic activity in vivo and mechanism of action.Specific work is as follows:A total of 34 new derivatives of 1,2,4-triazole and pyrimidines were synthesized from aminoguanidine bicarbonate and mitelic acid as starting materials.The structures of all compounds were confirmed by NMR and MS spectra.Compounds 10c,10d and10e showed high activity in MES and Sc-PTZ models.Compound 10c showed the highest activity in MES model.Its ED₅₀（8.51 mg/kg）was higher than the positive control drugs phenobarbital,phenytoin,carbamazepine and sodium valproate.Its protection index PI(TD₅₀/ED₅₀)was higher than phenobarbital and sodium valproate,but lower than phenytoin and carbamazepine.It also had higher activity in Sc-PTZ model(ED₅₀=31.62 mg/kg)than phenytoin,carbamazepine and sodium valproate.The study of structural-activity relationship showed that the length of carbon chain,fluorine atom and its position in benzene ring had direct influence on antiepileptic activity.Studies on the mechanism of action of active compound 10c showed that the anticonvulsant activity of compound 10c largely depended on its potentiation effect on GABA_A receptors,especially GABA_A1 and GABA_A4.Meanwhile,10c acts as a positive allosteric modulator of the GABA_A receptors at sites distinct from commonly used anticonvulsants benzodiazepines and barbiturates.Moreover,activity of 10c is more sensitive to subunit configurations in synapticα1β2γ2L and extrasynapticα4β3δGABA_Areceptors with the greatest response.Collectively,10c may exhibit a therapeutic advantage over benzodiazepines and barbiturates in various seizure indications,especially status epilepticus（SE）.Therefore,it is speculated that it has a good efficacy in the treatment of patients with tolerance to benzodiazepines and barbiturates.The activity of the active compound 10c onα1β2γ2L GABA_A receptor was further verified by molecular docking,which provides a theoretical basis for the design of 1,2,4-triazolopyrimidines.