Synthesis of benzimidazole-linked-1,3,4-oxadiazole carboxamides as GSK-3β inhibitors with in vivo antidepressant activity

Abstract Recent findings of potential implications of glycogen synthase kinase-3β (GSK-3β) dysfunction in psychiatric disorders like depression, have increased focus for development of GSK-3β inhibitors with possible anti-depressant activity. Keeping this in view, we synthesized a series of benzimidazole-linked-1,3,4-oxadiazole carboxamides and evaluated them for in vitro GSK-3β inhibition. Active compounds were investigated for in vivo antidepressant activity in Wistar rats. Docking studies of active compounds have also been performed. Among nineteen compounds synthesized, compounds 7a , 7r , 7j , and 7d exhibited significant potency against GSK-3β in sub-micromolar range with IC 50 values of 0.13 μM, 0.14 μM, 0.20 μM, 0.22 μM respectively and significantly reduced immobility time (antidepressant-like activity) in rats compared to control group. Docking study showed key interactions of these compounds with GSK-3β. These compounds may thus serve as valuable candidates for subsequent development of effective drugs against depression and related disorders.