The Study On The Synthesis And Anticonvulsant Activity Of 7-Azaindole Derivatives

As the common central nervous system disease,epilepsy seriously affects the normal life of patients,and anti-epilepsy drugs have many disadvantages such as low efficacy and high neurotoxicity.Hence,it is necessary to develop novel anti-epilepsy compounds with high activity and low neurotoxicity.Inspired by molecular hybridization,3-(1,2,3,6-tetrahydropyridine)-7-azazinole derivatives were designed and synthesized to study their antiepileptic activities,main works are as follows:Forty-one 3-substituted 7-azazindoles were synthesized and the structure were confirmed by NMR and MS.In cell experiments in vitro,29 compounds showed good inhibition on 4-AP-induced Ca²⁺oscillations shock,and the IC₅₀ values of?g,?p and?b ranged from 1.853-3.625?M.In the in vivo anticonvulsant activity model,compounds?g,?p and?b are specifically effective in sc-PTZ-induced epilepsy.And consistency of sc-PTZ animal model and cell model results of compounds?g,?p and?b proves the feasibility of cell model for preliminary screening of antiepileptic drugs.In sc-PTZ animal model,compound?g,?p and?b have higher anticonvulsant activity and lower neurotoxicity activity than the positive control carbamazepine and phenytoin sodium with ED₅₀ values 30.55 mg/kg,19.72mg/kg and 25.46 mg/kg,respectively,which prove the validity of the molecular hybridization method.In sc-PTZ model,the structure-activity relationship study indicated that 7-N and piperidine double bond in the 3-(1,2,3,6-tetrahydropyridine)-7-azazinole derivatives can improve anticonvulsant activity.In the N-amide-7-azaindole derivatives?,different length of carbon chain will cause different antiepileptic effect.In order to study the antiepileptic mechanism of the 7-azaindole anti-epilepsy derivatives,the compounds?g,?p and?b were docked on the GABA_A receptor whose results are consistent with the cell and animal experimental results in vitro and vivo.Therefore,it is speculated that compounds?g,?p and?b might inhibit epilepsy by docking on GABA_A targets.And further studies on the compounds?g,?p and?b on GABA_A targets will be conducted in the future to determine whether GABA_A receptors involved in antiepileptic effect.