Dibenzazepine-Linked Isoxazoles: New And Potent Class Of Alpha-Glucosidase Inhibitors

alpha-Glucosidase inhibition is a valid approach for controlling hyperglycemia in diabetes. In the current study, new molecules as a hybrid of isoxazole and dibenzazepine scaffolds were designed, based on their literature as antidiabetic agents. For this, a series of dibenzazepine-linked isoxazoles (33-54) was prepared using Nitrile oxide-Alkyne cycloaddition (NOAC) reaction, and evaluated for their alpha-glucosidase inhibitory activities to explore new hits for treatment of diabetes. Most of the compounds showed potent inhibitory potency against alpha-glucosidase (EC 3.2.1.20) enzyme (IC50 = 35.62 +/- 1.48 to 333.30 +/- 1.67 mu M) using acarbose as a reference drug (IC50 = 875.75 +/- 2.08 mu M). Structure-activity relationship, kinetics and molecular docking studies of active isoxazoles were also determined to study enzyme-inhibitor interactions. Compounds 33, 40, 41, 46, 48-50, and 54 showed binding interactions with critical amino acid residues of alpha-glucosidase enzyme, such as Lys156, Ser157, Asp242, and Gln353.