Synthesis And Anticonvulsant Activity Evaluation Of 6-alkoxytriazolo [4,3-a] Quinoxaline Derivatives

Epilepsy,one of the most frequent neurological afflictions characterized by irregular seizures and high unintentional mortality rate,dose harm to human health.Although the available antiepileptic drugs provide adequate seizure control in 70%of patients,30%of the patients with epilepsy are still not seizure free.Furthermore,many currently available AEDs have serious side effects on the blood and central nerve systems after long-term administration.Therefore,it is very meaningful to study and develop safer,more effective and novel AEDs.In this study,21 novel 6-alkoxy-[1,2,4]triazolo[4,3-a]quinoxaline derivatives(5a-5u)were designed and synthesized using 2,3-diaminopyridine as the starting material based on cyclization,chlorination,and hydrazine reaction.On the basis of them,a new series of 3-alkoxy-2-substituted pyrido[2,3-b]pyrazine containing other heterocycles was synthesized by the ring-opening and bioisosterism.All target compounds was confirmed by 1H-NMR,13C-NMR,IR,MS techniques.Their anticonvulsant activity and neurotoxicity were evaluated by the maximal electroshock(MES)test and rotarod test,respectively.The next work dose further study on anticonvulsant activity in pentylenetetrazol and bicuculline-induced seizures tests.The results on the pharmacology showed that the most of synthesized compounds had anticonvulsant activity and lower neurotoxicity at dose of 100 mg/kg.And the compounds containing triazole were better than the compounds linked triazole on anticonvulsant activity.However,at the dose of 30mg/kg,only a few compounds showed anticonvulsant activity.Among the compounds studied,6-phenoxy-pyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazine(5g)was the most potent compound,with a median effective dose(ED50)of 56.2 mg/kg and median toxicity dose(TD50)of 501.1 mg/kg,as well as the protective index(PI)value of 8.9.Although it was lower than carbamazepine on anticonvulsant activity,it was much safer than that of carbamazepine.According to the result of chemical-induced seizures,compound 5g can inhibited seizures induced by bicuculline,thus we speculated that it is possible mechanism of action including enhancing the function of GABAergic activity in the brain.