Hypoglycemic and Hypolipidemic Swords: Synthesis and In-vivo Biological Assessment of 5-benzylidene-2,4-thiazolidinediones

Thiazolidinedione (TZD), being a privileged scaffold, has been known as a significant structural moiety of antidiabetic drugs. TZD has been known to improve glycaemic control in type 2 diabetes mellitus (T2DM) by increasing insulin sensitivity in the body. A novel series of 5-benzylidene 2,4-thiazolidinedione derivatives were designed, synthesized (V1-V28), and structurally confirmed by different spectroscopic techniques such as FTIR, 1H NMR, 13C NMR, and Mass spectrometry. Upon the safety assessment of the synthesized molecules in non-transformed hepatocytes by MTT reduction assay, these were found non-toxic. These derivatives were then further evaluated for their antihyperglycemic and antihyperlipidemic properties in a high-fat diet and low dose of streptozotocin-induced diabetic rats. Altogether, seven biochemical parameters were analyzed, namely blood glucose, triglycerides, cholesterol, creatinine, blood urea nitrogen, HDL-cholesterol, and glycosylated hemoglobin in serum by standard methods. Four synthetic molecules (V2, V4, V5, and V20) possessed significant hypoglycaemic and hypolipidemic activity as compared to the positive control pioglitazone. Moreover, the histopathological studies of the heart and liver revealed no significant toxicity. Two representative compounds V2 and V4, were evaluated for their PPARγ activation potential, demonstrating that they were partial PPARγ agonists, thus confirming our designing hypothesis. Based on the results obtained, we assume that these compounds have the potential to be developed as future antidiabetic agents.