Design and synthesis of a novel quinoline thiazolidinedione hybrid as a potential antidiabetic PPARγ modulator.

Peroxisome proliferator-activated receptor γ (PPARγ) remains a critical target for antidiabetic drug development due to its role in glucose and lipid metabolism. However, the adverse effects associated with full agonists of the thiazolidinedione (TZD) class, such as weight gain and hepatotoxicity, limit their clinical utility. Herein, we report the design and synthesis of (Z)-5-benzylidene-3-((2-chloroquinolin-3-yl)methyl)thiazolidine-2,4-dione (compound 7), a novel TZD derivative that functions as a potential PPARγ modulator. Compound 7 reduced blood glucose level (BGL) by 22.33% after 15 days of treatment with a daily single oral dose, demonstrating an antidiabetic effect comparable to TZDs. Additionally, it elevated PPARγ expression to 75% of the activation level induced by Pioglitazone (PIO). Further characterization of its safety profile reveals that compound 7 is safer on the liver compared to PIO, as alanine transaminase (ALT) and aspartate transaminase (AST) levels remained significantly lower (147.4 ± 4.2 IU/L and 229.9 ± 2.7 IU/L, respectively). Moreover, compound 7 exerts a protective effect on hepatic and pancreatic tissues. Computational metabolic studies predict that compound 7 does not produce toxic metabolites or undergo hydrolysis of the TZD ring, contributing to its improved safety. The docking of Compound 7 into the PPARγ ligand-binding domain (LBD) demonstrates a unique binding mode, positioning it centrally within the LBD and interacting with key amino acids critical for selective modulation. These findings emphasize the potential of compound 7 as a selective PPARγ modulator to dissociate insulin-sensitizing effects from adverse side effects, offering a safer alternative to current TZD-based therapies.