2. Academic Validation
  3. Modulating glucose homeostasis via expression of PPAR-γ TF: Pharmacological insights into quinolone-based hydrazones

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

  • Eur J Med Chem. 2025 Dec 15:300:118168. doi: 10.1016/j.ejmech.2025.118168.
Naik Jui Pravin 1,  Rohini S Kavalapure 2,  Shankar Gharge 1,  Shankar G Alegaon 1,  Shriram D Ranade 3,  Rahul Koli 4,  B R Prashantha Kumar 5,  Sachin Gudasi 6,  Vilas Gowda K B 7,  Ramith Ramu 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi, 590 010, Karnataka, India.
  • 2 Department of Pharmaceutical Chemistry, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi, 590 010, Karnataka, India. Electronic address: [email protected].
  • 3 Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 576104, India.
  • 4 Department of Pharmaceutical Quality Assurance, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi, 590 010, Karnataka, India.
  • 5 Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru, JSS Academy of Higher Education and Research, Mysuru, 570015, Karnataka, India.
  • 6 Department of Pharmacognosy, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi, 590 010, Karnataka, India.
  • 7 Department of Biotechnology & Bioinformatics, JSS Academy of Higher Education & Research, Mysuru, 570015, Karnataka, India.
PMID: 40957268 DOI: 10.1016/j.ejmech.2025.118168
Abstract

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.

Keywords

Molecular dynamics simulations; Oral glucose tolerance; Peroxisome proliferator-activated receptor gamma; Quinolone; qRT-PCR.

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