Abstract
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•A series of dibenzazepine-linked isoxazoles was prepared using Nitrile oxide-Alkyne cycloaddition reaction as potent α-glucosidase inhibitors, which may act as hits for drug design and discovery of new anti-diabetic compounds.•Most of the compounds showed potent inhibition against α-glucosidase enzyme (IC50 = 35.62 ± 1.48 to 333.30 ± 1.67 µM) using acarbose as a reference drug (IC50 = 875.75 ± 2.08 µM).•Enzyme kinetic studies and molecular docking studies of synthesized isoxazoles were performed to study the enzyme-inhibitor interactions.
α-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 α-glucosidase inhibitory activities to explore new hits for treatment of diabetes. Most of the compounds showed potent inhibitory potency against α-glucosidase (EC 3.2.1.20) enzyme (IC50 = 35.62 ± 1.48 to 333.30 ± 1.67 µM) using acarbose as a reference drug (IC50 = 875.75 ± 2.08 µM). 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 α-glucosidase enzyme, such as Lys156, Ser157, Asp242, and Gln353.