Synthesis of heteroaryl/aryl kojic acid conjugates as stimulators of glucose uptake by GLUT4 translocation

Abstract

Insulin exerts its metabolic actions through the insulin receptor (IR) and plays an essential role in treatment of diabetes. The inconvenience of daily injections and the undesirable side-effects associated with insulin injections demand novel drugs for the disease. To search for bioactive insulin mimetic, we synthesized a chemical library of small molecules (2a–3f) based on the indolylkojic acid scaffold (B). An In vitro screening assay was performed to stimulate glucose transport in rat L6 skeletal muscle cells, post treatment of the compounds (2a–3f) for the time period incubation of 16 h. Compounds 2f, 2g, 2l, 3a, 3b, 3c and 3d have shown significant glucose uptake stimulation as compared to the controls at micromolar concentrations. In mechanistic studies, we observed that these compounds exert their biological action by enhancing GLUT4 translocation to cell surface via PI3K-dependent signalling pathway in agreement to the insulin mode of action. Hence, these promising conjugates should be useful for further drug development in diabetes treatment.