Design, synthesis and anti-diabetic activity of piperazine sulphonamide derivatives as dipeptidyl peptidase-4 inhibitors

Abstract

Type II diabetes (T2DM) is considered one of the most prevalent metabolic disorders in the world. It is known as insulin resistance and persistent hyperglycemia. Over the past decade, inhibition of the enzymatic dipeptidyl peptidase-4 (DPP-4) has indeed been demonstrated to be an efficient and safe intervention for type 2 diabetes. In order to develop innovative DPP-4 inhibitors, several in silico techniques including 3D-QSAR, molecular docking, in-silico toxicity has been performed to confirm a total of 18 novel piperazine and pyridine derivatives to be synthesized from many designed molecules. These molecules have indeed been docked onto the protein surface of the DPP-4 enzyme, and ADMET characteristics have also been generated in silico. The compounds were then developed and analysed using FT-IR. Then, these compounds were investigated for DPP-4 inhibition in vitro. The most promising compound 8h showed 27.32% inhibition at 10μmol L-1 concentration over DPP-4 so selected for further in-vivo anti-diabetic evaluation. Compound 8h decreased blood glucose excursion in a dose-dependent manner during the OGTT and STZ-induced glucose models in normal Albino Wistar rats. Low-dose streptozotocin-induced type 2 diabetes in Albino Wistar rats treated chronically for 21 days with compound 8h resulted in a reduction in serum glucose levels. This highlighted that 8h is a moderately strong and specific blockbuster molecule that can be structurally modified to boost its effectiveness and overall pharmacological profile as a DPP-4 inhibitor.