Synthesis and studies of thiazolidinedione derivatives as potential antidiabetic agents

Abstract

Diabetes mellitus is a general term for heterogeneous disturbances of metabolism characterized by persistent hyperglycemia, resulting from deficiency in insulin secretion, impaired insulin action or a combination of both. and#945;-Glucosidase plays an important role in the carbohydrate digestion and glycoprotein processing. In humans, these enzymes help in the production of glucose for intestinal absorption by digesting dietary carbohydrate and starch. Prevention of intestinal digestion and absorption of carbohydrates via inhibition of carbohydrate-hydrolyzing enzymes is one of the strategies to manage postprandial plasma glucose level. and#945;-Glucosidase inhibition has emerged as promising therapeutic approach for the management of T2DM. Due to the side effects associated with clinically available and#945;-Glucosidase inhibitiors (AGIs), there is a need to explore and develop new, potent AGIs with reduced side effects. From the literature survey, it was also evident that arylidene TZD, alkyl/aryl/substituted aryl, sulfonyl, and N-substituted moieties have made considerable contribution towards the and#945;-Glucosidase inhibition. Based upon these observations, three series of TZD based molecules were designed, synthesized and characterized by 1H NMR, 13C NMR and Mass spectrometry. Synthesized compounds were evaluated for and#945;-Glucosidase inhibition potential by in vitro method. Most of the synthesized hybrids were found to have many folds better potency than acarbose. Two potent compounds from each series were subjected to in vivo disaccharide loading test. Results outcome of these studies are indicative of antidiabetic potential of synthesized compounds compared to standard drug acarbose tested at dose of 20 mg/kg body weight. Cytotoxicity studies were carried out to determine the safety of potent compounds towards normal cells and revealed the safety of compounds. Computer aided in silico studies, such as, molecular docking and predictive pharmacokinetic studies further justified the results of in-vitro and in-vivo biological evaluation.