Towards multi-target antidiabetic agents: In vitro and in vivo evaluation of 3,5-disubstituted indolin-2-one derivatives as novel α-glucosidase inhibitors
| Autor: | Denis A. Babkov, Ekaterina V. Zaryanova, Alexander A. Spasov, N. A. Lozinskaya, Meriam Dubar, Daria D. Melekhina, V. V. Temnov, E.N. Bezsonova, Vladlen G. Klochkov |
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| Rok vydání: | 2021 |
| Předmět: |
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Molecular Indoles Clinical Biochemistry Pharmaceutical Science Type 2 diabetes Pharmacology Biochemistry chemistry.chemical_compound Structure-Activity Relationship In vivo Diabetes mellitus Drug Discovery medicine Potency Humans Hypoglycemic Agents Glycoside Hydrolase Inhibitors Molecular Biology IC50 Dose-Response Relationship Drug Molecular Structure Organic Chemistry alpha-Glucosidases Maltose medicine.disease In vitro Postprandial chemistry Diabetes Mellitus Type 2 Molecular Medicine |
| Zdroj: | Bioorganicmedicinal chemistry letters. 55 |
| ISSN: | 1464-3405 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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