Novel Thiazolidinedione Derivatives as effective agonists of Peroxisome Proliferator Activator Receptor-γ: A Comprehensive Study on Design, Synthesis, Molecular Docking, MD Simulations, and Antidiabetic Efficacy

Abstract

Abstract In the quest for potential anti-diabetic agents, a novel series of thiazolidinedione derivatives (2a-j)were synthesized and characterized by spectroscopic data. These newly developed derivatives were subjected to molecular docking studies, utilizing the binding pocket of the Peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, to understand their binding interactions. To assess the stability of the ligand-PPAR-γ complex, molecular dynamics (MD) simulations were conducted for synthesized compounds. The cytotoxicity of the compounds was evaluated in C2C12 myoblasts using the MTT assay. Additionally, the compounds were tested on C2C12 cell lines to confirm their PPAR-γ transcription activity. Furthermore, the synthesized compounds underwent evaluation for their in vivo blood glucose-lowering activity using a dexamethasone-induced diabetic rat model. Significantly, compounds 2b, 2g, and 2h demonstrated potential as PPAR-γ agonists compared to the reference drug Pioglitazone. Data analysis revealed noteworthy blood glucose-lowering effects (hypoglycaemia) for compounds 2b, 2g, and 2h (110.04±5.42, 114.52±6.32, and 118.48±5.93, respectively), as well as for the reference drug Pioglitazone (153.93±4.61), when compared to the diabetic control. Moreover, compounds 2b, 2g, and 2h exhibited significant reductions in the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP), indicating the absence of liver damage.