New prospects for the development of selective inhibitors of α-glucosidase based on coumarin-iminothiazolidinone hybrids: Synthesis, in-vitro biological screening and molecular docking analysis

alpha-Glucosidase inhibitors have extensively been exploited for the effective management of type 2 diabetes and associated complications by significantly reducing the postprandial increase in glucose and plasma insulin levels. In this endeavour, we designed and synthesized a new series of coumarinyl iminothiazolidinone hybrid compounds (6a-o) using a one-pot multi-component approach. The hybrid structures were accessed in good chemical yields. The synthesized compounds were tested for their glucosidase inhibitory efficacy using acarbose as a standard inhibitor (IC50 = 38.2 +/- 0.12 mu M). In-vitro analysis of the hybrid molecules identified several potential leads for the development of potent glucosidase inhibitors with IC50 values in the range of 0.09-0.92 mu M with compound 6g being the most potent drug candidate (IC50 = 0.09 +/- 0.001 mu M). Furthermore, compound 6f was identified as the lead inhibitor against maltase-glucoamylase with comparable inhibitory efficacy to acarbose with an IC50 value of 0.07 +/- 0.016 mu M. Binding interactions of potent compounds with the key residues in the active site of the glucosidase enzyme were revealed by molecular docking analysis. In summary, these new structural leads based on the hybrid pharmacophores could be developed as potential inhibitors of alpha-glucosidase for treating postprandial hyperglycemia. (C) 2017 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.