Abstract
A series of aryl anilinomaleimide based derivatives has been synthesized and evaluated for in vitro glycogen synthase kinase-3 beta (GSK-3 beta) inhibitory activity. A large number of compounds from the series exhibited moderate to potent inhibitory activity against GSK-3 beta, with more than one-third of the compounds showing inhibition with IC50 values <1 mu M. The molecular docking studies against GSK-3 beta (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 p-cation interactions by some compounds. Given the potential role of GSK-3 beta inhibition in the treatment of depression, compounds 8j, 8b, 8i, 8l, 8a and 8n, exhibiting significant GSK-3b inhibition (IC50 values of 0.09, 0.12, 0.17, 0.19, 0.21 and 0.23 mu M 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.