A new entry into the portfolio of α-glucosidase inhibitors as potent therapeutics for type 2 diabetes: Design, bioevaluation and one-pot multi-component synthesis of diamine-bridged coumarinyl oxadiazole conjugates

Diabetes mellitus (DM), a chronic multifarious metabolic disorder resulting from impaired glucose home-ostasis has become one of the most challenging diseases with severe life threat to public health. The inhibition of alpha-glucosidase, a key carbohydrate hydrolyzing enzyme, could serve as one of the effective methodology in both preventing and treating diabetes through controlling the postprandial glucose levels and suppressing postprandial hyperglycemia. In this context, three series of diamine-bridged bis-coumarinyl oxadiazole conjugates were designed and synthesized by one-pot multi-component methodology. The synthesized conjugates (4a-j, 5a-j, 6a-j) were evaluated as potential inhibitors of glucosidases. Compound 6f containing 4,4'-oxydianiline linker was identified as the lead and selective inhibitor of alpha-glucosidase enzyme with an IC50 value of 0.07 +/- 0.001 mu M (acarbose: IC50 = 38.2 +/- 0.12 mu M). This inhibition efficacy was similar to 545-fold higher compared to the standard drug. Compound 6f was also emerged as the lead molecule against intestinal maltase-glucoamylase with good inhibition strength (IC50 = 0.04 +/- 0.02 mu M) compared to acarbose (IC50 = 0.06 +/- 0.01 mu M). Against beta-glucosidase enzyme, compound 6 g was noted as the lead inhibitor with IC50 value of 0.08 +/- 0.002 mu M. Michaelis-Menten kinetic experiments were performed to explore the mechanism of inhibition. Molecular docking studies of the synthesized library of hybrid structures against glucosidase enzyme were performed to describe ligand-protein interactions at molecular level that provided an insight into the biological properties of the analyzed compounds. The results suggested that the inhibitors could be stabilized in the active site through the formation of multiple interactions with catalytic residues in a cooperative fashion. In addition, strong binding interactions of the compounds with the amino acid residues were effective for the successful identification of alpha-glucosidase inhibitors. (C) 2018 Elsevier Inc. All rights reserved.