Synthesis and biological evaluation of 3-substituted 2-oxindole derivatives as new glycogen synthase kinase 3β inhibitors

Glycogen synthase kinase 3 beta (GSK-3 beta) is a widely investigated molecular target for numerous diseases including Alzheimer's disease, cancer, and diabetes mellitus. Inhibition of GSK-3 beta activity has become an attractive approach for treatment of diabetes and cancer. We report the discovery of novel GSK-3 beta inhibitors of 3-arylidene-2-oxindole scaffold with promising activity. The most potent compound 3a inhibits GSK-3 beta with IC(50 )4.19 nM. In a cell-based assay 3a shows no significant leucocyte toxicity at 10 mu 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 50 mg/kg body weight thus representing an interesting lead for further optimization.