Design, synthesis, characterization, and molecular modeling studies of novel oxadiazole derivatives of nipecotic acid as potential anticonvulsant and antidepressant agents

A series of fifteen novel nipecotic acid 1,3,4-oxadiazole hybrids were synthesized with the intent to improve the lipophilicity of nipecotic acid and its penetration through the blood-brain barrier (BBB). The structures of the compounds were established by FT-IR, H-1-NMR, C-13-NMR, and elemental analysis. The effect of the synthesized compounds was assessed on motor coordination using the rotarod test in mice. Anticonvulsant activity was evaluated using the subcutaneous pentylenetetrazol (scPTZ) test in mice. Five compounds (5d, 5e, 5g, 5m, and 5o) exhibited significant protection against scPTZ-induced seizures. None of the compounds produced any disruption in motor coordination as observed in the rota-rod test, nor did they elevate the serum levels of biochemical markers related to hepatic and renal toxicity, affirming their relative safety. The derivatives also exhibited significant antidepressant activity, devoid of serotonergic augmentation as assessed using the despair swim test, 5-hydroxytryptophan (5-HTP)-induced head twitch test and learned helplessness test. In in silico docking studies on a homology model on target GABA transporter 1 (GAT1) protein and the most active compound 5e helped to identify critical enzyme-ligand interactions leading to the inhibition of the GAT1 transporter.