Design,Synthesis And Antiepileptic Activity Of 4-Azaindole Derivatives

Epilepsy is a chronic neurological disease that seriously affects the health of about1%of the world’s population.Currently,most epilepsy treatment drugs have shortcomings such as low activity,large toxic and side effects,and unclear targets.Therefore,it is crucial to find more safe and effective antiepileptic active compounds,especially those with clear action targets.Three 7-azaindole compounds with high activity but low safety and unknown target were found to be more safe antiepileptic compounds by molecular hybridization strategy.Based on these compounds,4-azaindole derivatives with similar structure were designed and synthesized according to the principle of bioelectron equiarrangement in pharmaceutical chemistry,and their antiepileptic activity and target were tested,main works are as follows:Forty-eight 3-（1,2,3,6）-tetrahydropyridine-4-azaindole derivatives were synthesized from 4-azaindole and N-Boc-4-piperidone and the structure was confirmed by NMR and MS.In the 4-AP induced epilepsy model,20 compounds showed good antiepileptic activity.In vivo antiepileptic activity test showed that all the compounds had no antiepileptic activity in MES model.In sc-PTZ induced epilepsy model,the ED₅₀ values of compoundsⅣw andⅤi were 22.01 and 25.26 mg/kg,TD₅₀ values were higher than 600mg/kg and PI values were higher than 27.26 and 23.75,respectively.Compared with the positive control drugs valproate(ED₅₀=239.4 mg/kg,PI=1.56)and ethosuximide(ED₅₀=106.0 mg/kg,PI=3.2),they had higher antiepileptic activity and lower neurotoxicity.In addition,the protective indices(TD₅₀/ED₅₀)of compoundsⅣw andⅤi are also significantly higher than those of 7-azaindole derivativesⅢg（PI=8.58）,Ⅲp（PI=10.29）andⅣb（PI=7.41）,which fully prove the effectiveness of structural optimization using the principle of electron equiarrangement.The pharmacokinetic properties of active compoundsⅣw andⅤi predicted by ADMETlab2.0 online platform indicate thatⅣw andⅤi have higher oral bioavailability and better ability to cross the blood-brain barrier.The study of structure-activity relationship shows that the nitrogen atoms at 4 and7 positions in the skeleton of azaindole,the hydrogen atoms on the NH group in the pyrrole ring and the double bond of 1,2,3,6-tetrahydropyridine are essential active fragments for antiepileptic activity.The carbon chain length of acyl group in N-amido-4-azaindole derivatives IV has different effects on antiepileptic activity,in which the compound IVw with carbon chain length of 8 has the best antiepileptic activity and the existence of carbonyl oxygen atom in compound IVw is beneficial to inhibit epileptic seizures.This may be due to the lone pair electron on oxygen atom and the electron cloud density on acyl group enhance the binding of compounds to receptors,thus improving the antiepileptic activity of compounds.In N-amino-4-azaindole derivative V,when the same substituent group is located at different positions in the benzene ring,it has a significant impact on the activity,where o-CF₃<m-CF₃<p-CF₃.Molecular docking studies showed that compoundsⅣw andⅤi had hydrogen bonds with sodium channel receptors,which enhanced the binding between compounds and receptors.It was speculated that compoundsⅣw andⅤi were related to voltage-gated sodium channels and confirmed at the cellular level.The antiepileptic activity of compoundsⅣw andⅤi depends on the inhibition of voltage-gated sodium channels.