51. Design and synthesis of novel xanthone-triazole derivatives as potential antidiabetic agents: α-Glucosidase inhibition and glucose uptake promotion.
- Author
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Ye GJ, Lan T, Huang ZX, Cheng XN, Cai CY, Ding SM, Xie ML, and Wang B
- Subjects
- Binding Sites, Drug Design, Glycoside Hydrolase Inhibitors chemical synthesis, Glycoside Hydrolase Inhibitors metabolism, Glycoside Hydrolase Inhibitors toxicity, Hep G2 Cells, Hepatocytes drug effects, Humans, Hypoglycemic Agents chemical synthesis, Hypoglycemic Agents metabolism, Hypoglycemic Agents toxicity, Kinetics, Molecular Docking Simulation, Molecular Structure, Protein Binding, Structure-Activity Relationship, Triazoles chemical synthesis, Triazoles metabolism, Triazoles toxicity, Xanthones chemical synthesis, Xanthones metabolism, Xanthones toxicity, alpha-Glucosidases chemistry, alpha-Glucosidases metabolism, Glucose metabolism, Glycoside Hydrolase Inhibitors pharmacology, Hypoglycemic Agents pharmacology, Triazoles pharmacology, Xanthones pharmacology
- Abstract
Inhibiting the decomposition of carbohydrates into glucose or promoting glucose conversion is considered to be an effective treatment for type 2 diabetes. Herein, a series of novel xanthone-triazole derivatives were designed, synthesized, and their α-glucosidase inhibitory activities and glucose uptake in HepG2 cells were investigated. Most of the compounds showed better inhibitory activities than the parental compound a (1,3-dihydroxyxanthone, IC
50 = 160.8 μM) and 1-deoxynojirimycin (positive control, IC50 = 59.5 μM) towards α-glucosidase. Compound 5e was the most potent inhibitor, with IC50 value of 2.06 μM. The kinetics of enzyme inhibition showed that compounds 5e, 5g, 5h, 6c, 6d, 6g and 6h were noncompetitive inhibitors, and molecular docking results were consistent with the noncompetitive property that these compounds bind to allosteric sites away from the active site (Asp214, Glu276 and Asp349). On the other hand, the glucose uptake assays exhibited that compounds 5e, 6a, 6c and 7g displayed high activities in promoting the glucose uptake. The cytotoxicity assays showed that most compounds were low-toxic to human normal hepatocyte cell line (LO2). These novel xanthone triazole derivatives exhibited dual therapeutic effects of α-glucosidase inhibition and glucose uptake promotion, thus they could be use as antidiabetic agents for developing novel drugs against type 2 diabetes., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)- Published
- 2019
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