Towards multi-target antidiabetic agents: In vitro and in vivo evaluation of 3,5-disubstituted indolin-2-one derivatives as novel α-glucosidase inhibitors.
|
| Abstract |
Type 2 diabetes mellitus is a chronic progressive disease that usually requires polypharmacological treatment approaches. Previously we have described a series of 2-oxindole derivatives as GSK3β inhibitors with in vivo antihyperglycemic activity. α-Glucosidase is another antidiabetic target that prevents postprandial hyperglycemia and corresponding hyperinsulinemic response. Herein we report a study of 3,5-disubstituted indolin-2-one derivatives as potent α-glucosidase inhibitors. These inhibitors were identified via efficient synthesis, in vitro screening, and biological evaluation. The most active compound 5f inhibits yeast α-glucosidase with IC50 of 6.78 µM and prevents postprandial hyperglycemia in rats after maltose and sucrose challenge at 5.0 mg/kg dose. Two lead glucosidase inhibitors, 5f and 5m, are also GSK3β inhibitors with submicromolar potency. Hence, structure-activity studies elucidate foundation for development of dual GSK3β/α-glucosidase inhibitors for treatment of type 2 diabetes.
|
|---|---|
| Authors | Vladlen G Klochkov, Elena N Bezsonova, Meriam Dubar, Daria D Melekhina, Victor V Temnov, Ekaterina V Zaryanova, Natalia A Lozinskaya, Denis A Babkov, Alexander A Spasov |
| Journal | Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 55 Pg. 128449 (01 01 2022) ISSN: 1464-3405 [Electronic] England |
| PMID | 34780899 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2021 Elsevier Ltd. All rights reserved. |
| Chemical References |
|
| Topics |
|
Join CureHunter, for free Research Interface BASIC access!
Realize the full power of the drug-disease research graph!