Modulating glucose homeostasis via expression of PPAR-γ TF: Pharmacological insights into quinolone-based hydrazones

The growing prevalence of type 2 diabetes underscores the urgent need for novel therapeutic agents targeting glucose homeostasis and insulin sensitivity. In this study, a new series of quinolone-based hydrazone derivatives (7a-7k) was synthesized and evaluated for their ability to modulate peroxisome proliferator-activated receptor gamma (PPAR-γ), a key regulator of glucose and lipid metabolism. Among them, compounds 7c and 7e showed strong, concentration-dependent activation of PPAR-γ in HepG2 and L6 myotube cell lines, comparable to pioglitazone. In vivo studies using STZ-nicotinamide-induced diabetic rats confirmed their efficacy, with 7e significantly lowering fasting blood glucose, improving glucose tolerance, and restoring metabolic balance. Histopathological analysis revealed protection of pancreatic islets, hepatocytes, skeletal muscle, and adipose tissue. Molecular studies further demonstrated upregulation of Pparg, Glut4, and AdipoQ, alongside suppression of TNF-α, IL-6, and NF-κB p65, highlighting both insulin-sensitizing and anti-inflammatory effects. Docking and 100 ns molecular dynamics simulations validated the stable binding of 7c and 7e within the PPAR-γ ligand-binding domain. Collectively, these findings identify 7c and 7e as promising multifunctional candidates for type 2 diabetes management through dual regulation of glucose homeostasis and inflammation.