Thiazolidine based novel antidiabetic agents design synthesis and biological investigations

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder typically characterized by hyperglycemia. Management of the hyperglycemia basically involves the reduction of hepatic glucose production, enhancement of insulin action, intensification of insulin secretion from and#946;-pancreatic cells or inhibition of carbohydrate digestive enzymes. and#945;-Glucosidase, a carbohydrate digestive enzyme, plays a vital role in the lysis of the and#945;-glucopyranoside bond in disaccharides and oligosaccharides to release absorbable monosaccharides and thus regulates the degree of postprandial hyperglycemia. Four series of thiazolidine based hybrids were designed, synthesized and characterized by spectroscopic techniques. Most of the synthesized compounds have shown potent in vitro and#945;-glucosidase inhibition i.e. many folds better than reference standard acarbose. Three most potent derivatives were further investigated for cell toxicity against normal cell lines and observed to be safe. In vivo disaccharide loading test of three potent compounds ratified their higher efficacy over acarbose at a dose of 20 mg/kg of body weight. Additionally, compounds possessed antioxidant properties which may contribute towards the management of oxidative stress mediated complications in T2DM. In silico procedures i.e. homology modelling, molecular docking, molecular dynamic simulations, binding free energy calculations and ADME predictive studies further justified the results of in vitro and in vivo biological investigations. newline