Towards multi-target antidiabetic agents: In vitro and in vivo evaluation of 3,5-disubstituted indolin-2-one derivatives as novel α-glucosidase inhibitors

Bioorg Med Chem Lett. 2022 Jan 1;55:128449. doi: 10.1016/j.bmcl.2021.128449. Epub 2021 Nov 12.


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.

Keywords: Diabetes mellitus; Indolin-2-one; Oxindoles; α-Glucosidase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Dose-Response Relationship, Drug
  • Glycoside Hydrolase Inhibitors / chemical synthesis
  • Glycoside Hydrolase Inhibitors / chemistry
  • Glycoside Hydrolase Inhibitors / pharmacology*
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • alpha-Glucosidases / metabolism*


  • Glycoside Hydrolase Inhibitors
  • Hypoglycemic Agents
  • Indoles
  • indolin-2-one
  • alpha-Glucosidases