Design, synthesis and anti-hyperglycemic assessments of novel 5-benzyli-denethiazolidine-2,4-dione derivatives as PPAR-? agonist

The treatment of diabetes mellitus still relies predominantly on peroxisome proliferator-activated receptor-gamma (PPAR-gamma) therapy, known for its effectiveness. In this present study, a novel series of benzylidene-linked thia-zolidine-2,4-dione compounds was conceptualized, synthesized, and subjected to assessment for their potential antidiabetic properties. Notably, among the compounds examined, 5-((Z)-4-(((E)-Propylidene)amino)benzyli-dene)thiazolidine-2,4-dione, designated as 4c, emerged as the most promising candidate, exhibiting the highest PPAR-gamma agonistic activity with an EC50 value of 0.35 +/- 0.52 mu M. Additionally, molecular docking investigations were conducted on twelve 2,4-thiazolidinedione compounds, with a pyrazole moiety incorporated, within the ligand binding domain of PPAR-gamma. Compound 4c, in particular, demonstrated a Glide XP score of-9.104, sur-passing the score of the crystal ligand (Glide XP score =-7.482). Notably, both exhibited similar interactions with key amino acids, including HIE323, SER289, and GLN286. Furthermore, three derivatives (4a-c) with promising PPAR-gamma agonistic activity and favorable molecular docking scores underwent in vivo evaluation for their capacity to lower blood glucose levels using a streptozotocin-induced diabetic mice model. In comparison to the reference drug pioglitazone, Compound 4c displayed commendable in-vivo performance across multiple parameters, encompassing serum HDL, serum LDL, serum total cholesterol, and serum triglyceride levels. Mo-lecular dynamics simulations provided insights into the impact of ligand 4c, indicating its role in enhancing protein stability and rigidity. These findings emphasize its potential as a potent protein inhibitor, thus opening novel avenues for the intelligent design of molecules with high efficacy in the management of hyperglycemia.