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Bioorg Med Chem Lett ; 40: 127979, 2021 05 15.
Article in English | MEDLINE | ID: mdl-33766763

ABSTRACT

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.


Subject(s)
Dibenzazepines/chemistry , Glycoside Hydrolase Inhibitors/chemistry , Hypoglycemic Agents/chemistry , Isoxazoles/chemistry , 3T3 Cells , Animals , Cycloaddition Reaction , Dibenzazepines/chemical synthesis , Dibenzazepines/toxicity , Enzyme Assays , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/toxicity , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/toxicity , Isoxazoles/chemical synthesis , Isoxazoles/toxicity , Kinetics , Mice , Molecular Docking Simulation , Molecular Structure , Oligo-1,6-Glucosidase/metabolism , Protein Binding , Saccharomyces cerevisiae/enzymology , Saccharomyces cerevisiae Proteins/metabolism , Structure-Activity Relationship
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