Abstract

The clinically used glitazones for the management of type 2 diabetes mellitus are full agonists of peroxisome proliferator activated receptors (PPAR)-γ and potent insulin sensitizers. Unfortunately, these molecules suffered from various side effects which resulted in their restriction/ban. Various new strategies were, therefore, developed to overcome the existing problems with the full agonists. Among them the development of partial and dual PPAR agonists are some of the important strategies adopted to improve the adverse profiles of the full agonists. In the present study, 11 novel (5Z)-5- [4-(3-phenoxypropoxy)benzylidene]-1,3-thiazolidine-2,4-dione derivatives were designed, synthesized and evaluated for their possible partial and dual agonistic activities using in silico and in vitro methods. The in silico docking and in vitro PPAR-α & γ competitive binding studies confirm the dual binding potential of these molecules. The post docking analysis reveals that the molecules, 4a, 4b, 4c, 4d, 4e, 4h and 4j, exhibit binding modes similar to a full agonist and molecules, 4f, 4g, 4i and 4k, show binding modes similar to a partial agonist of PPAR-γ receptors. On PPAR-α receptors, all the molecules except, 4a and 4g, show binding modes similar to a full agonist, The molecules, 4a and 4g, however, show binding modes similar to that of a partial agonist. Further, in the in vitro 3T3L1 preadipocytes assay, all the molecules promote the adipocyte differentiation confirming their PPAR-γ agonistic activity. These molecules, therefore, show potential to overcome the problems of the clinically used glitazones in the management of type 2 diabetes mellitus.

Keywords: Dual PPAR agonists, Glitazones, PPAR-α, PPAR-γ, PPAR-δ, Type 2 diabetes mellitus, Thiazolidines-2, 4-diones.