Design, synthesis, anticonvulsant activity and structure-activity relationships of novel 7-Azaindole derivatives

In search of new-structure compounds with good anticonvulsant activity and low neurotoxicity, a series of 3-(1,2,3,6-tetrahydropyridine)-7-azaindole derivatives was designed and synthesized. Their anticonvulsant activities were evaluated by maximal electroshock (MES) and pentylenetetrazole (PTZ) test, and neurotoxicity was determined by the rotary rod method. In the PTZ-induced epilepsy model, compounds 4i, 4p and 5 k showed significant anticonvulsant activities with ED₅₀ values at 30.55 mg/kg, 19.72 mg/kg and 25.46 mg/kg, respectively. However, these compounds did not show any anticonvulsant activity in the MES model. More importantly, these compounds have lower neurotoxicity with protective index (PI = TD₅₀/ED₅₀) values at 8.58, 10.29 and 7.41, respectively. In order to obtain a clearer structure-activity relationship, more compounds were designed rationally based on 4i, 4p and 5 k and their anticonvulsant activities were evaluated on PTZ models. The results demonstrated that the N-atom at the 7-position of the 7-azaindole and the double-bond in the 1,2,3,6-tetrahydropyridine skeleton was essential for antiepileptic activities.