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 GSK3ß 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 GSK3ß inhibitors with submicromolar potency. Hence, structure-activity studies elucidate foundation for development of dual GSK3ß/α-glucosidase inhibitors for treatment of type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glycoside Hydrolase Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Indoles/pharmacology , alpha-Glucosidases/metabolism , Diabetes Mellitus, Type 2/metabolism , Dose-Response Relationship, Drug , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Glycogen synthase kinase 3ß (GSK-3ß) is a widely investigated molecular target for numerous diseases including Alzheimer's disease, cancer, and diabetes mellitus. Inhibition of GSK-3ß activity has become an attractive approach for treatment of diabetes and cancer. We report the discovery of novel GSK-3ß inhibitors of 3-arylidene-2-oxindole scaffold with promising activity. The most potent compound 3a inhibits GSK-3ß with IC50 4.19â¯nM. In a cell-based assay 3a shows no significant leucocyte toxicity at 10⯵M and is moderately cytotoxic against A549 cells. Compound 3a demonstrated high antidiabetic efficacy in obese streptozotocin-treated rats improving glucose tolerance at a dose of 50â¯mg/kg body weight thus representing an interesting lead for further optimization.
Subject(s)
Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Oxindoles/chemistry , Protein Kinase Inhibitors/chemical synthesis , A549 Cells , Animals , Binding Sites , Catalytic Domain , Cell Survival/drug effects , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/drug therapy , Glucose Tolerance Test , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Oxindoles/pharmacology , Oxindoles/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Rats , Structure-Activity RelationshipABSTRACT
The study represents the new findings at the crossroads of chemistry and medicine, particularly between medicinal and organic chemistry and ophthalmology. In this work we describe how the chemical reactivity of indolinone scaffold may be used to create small molecule ligands with strong biological response comparable with and larger than that of endogenous hormone. The synthesis of oxindole-based melatonin and 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) analogues was proposed and their ability to influence intraocular pressure (IOP) was studied in vivo. Time-dependent study revealed the prolonged effect (more than 6h) of the lead-compound. This effect in combination with high IOP reducing effect (41±6%) in low concentrations of the active compound (0.1wt%) and with high water solubility represents a great potential of low-cost oxindole derivatives as potent antiglaucoma agents.
