Molecular modeling design, synthesis, and anti-hyprglycemic evaluation of certain 5-(aryl-alkoxy-benzylidine)-imidazolidine-2,4-dione derivatives as potential PPARγ agonists

A series of novel substituted 5-(aryl-alkoxy-benzylidine)-imidazolidine-2,4-diones (4a-f, 5a) were designed and evaluated as selective PPAR gamma agonists analogous to the reference lead, rosiglitazone (II). The molecular modeling compare/Fit study of these molecules with the PPAR gamma agonists' pharmacophore constructed from known PPAR gamma agonists and the docking scores of the same designed molecules using the 3D protein crystal structure of the PPAR gamma receptors were determined. The fit scores of these molecules were more or less similar to the reference drug (II), while the reduced molecule 5a gave highest fit value. The docking scores of molecules 4c-f and 5a were higher than the lead II. These hit molecules were subsequently synthesized and evaluated for their in vivo anti-hyperglycemic activity in hyperglycemic animal model. Compounds 4a-e showed similar or slightly higher activity than the lead drug II. In contrast, the activities of compounds 4f and 5a were 1.2- and 1.3-folds higher than the same lead.