Synthesis of aryl anilinomaleimide based derivatives as glycogen synthase kinase-3β inhibitors with potential role as antidepressant agents

Abstract

A series of aryl anilinomaleimide based derivatives has been synthesized and evaluated for in vitro glycogen synthase kinase-3β (GSK-3β) inhibitory activity. A large number of compounds from the series exhibited moderate to potent inhibitory activity against GSK-3β, with more than one-third of the compounds showing inhibition with IC₅₀ values <1 μM. The molecular docking studies against GSK-3β (PDB: 1Q3D) revealed multiple H-bonding interactions of the synthesized molecules with important amino acid residues on the receptor site, in addition to H-bonding with water residues and π-cation interactions by some compounds. Given the potential role of GSK-3β inhibition in the treatment of depression, compounds 8j, 8b, 8i, 8l, 8a and 8n, exhibiting significant GSK-3β inhibition (IC₅₀ values of 0.09, 0.12, 0.17, 0.19, 0.21 and 0.23 μM respectively), were further investigated for antidepressant activity by the widely accepted forced swim test and tail suspension test (FST and TST) models. All the tested compounds displayed antidepressant-like effects, particularly compounds 8j and 8b, which exhibited significant antidepressant activity, about 1.4-fold higher than fluoxetine, a standard antidepressant drug in both FST and TST. Preliminary structure–activity relationships have also been generated based on the experimental data obtained.