Design, synthesis and anti-hyperglycemic assessments of novel 5-benzylidenethiazolidine-2,4-dione derivatives as PPAR-γ agonist

Abstract

The treatment of diabetes mellitus still relies predominantly on peroxisome proliferator-activated receptor-γ (PPAR-γ) therapy, known for its effectiveness. In this present study, a novel series of benzylidene-linked thiazolidine-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)benzylidene)thiazolidine-2,4-dione, designated as 4c, emerged as the most promising candidate, exhibiting the highest PPAR-γ agonistic activity with an EC50 value of 0.35 ± 0.52 μM. Additionally, molecular docking investigations were conducted on twelve 2,4-thiazolidinedione compounds, with a pyrazole moiety incorporated, within the ligand binding domain of PPAR-γ. Compound 4c, in particular, demonstrated a Glide XP score of −9.104, surpassing 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-γ 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. Molecular 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.