Expression of PPAR-γ TF by newly synthesized thiazolidine-2,4-diones to manage glycemic control: Insights from in silico, in vitro and experimental pharmacology in wistar rats

In pursuit of novel antidiabetic agents to combat type II diabetes mellitus, our study focused on identifying pharmacophoric features responsible for PPAR-γ expression, a key regulator of glucose homeostasis and lipid metabolism. This goal was achieved through pharmacophore model generation and screening of rationally designed library of thiazolidine-2,4-dione hybrids (7a-7f). The top hits were synthesized, characterized, and evaluated for their in vitro and in vivo antidiabetic activities. Among these, compounds 7b and 7c emerged as promising candidates, exhibiting significant in vitro inhibitory activity against human pancreatic α-amylase (HPA) and human liver α-glucosidase (HLAG) Enzymes, along with enhanced glucose uptake in L6 myotube cell lines. Specifically, compound 7b showed 29.04 ± 1.13 µM HPA inhibition, 34.21 ± 1.16 µg/mL HLAG inhibition, and 77.12 ± 1.02 % glucose uptake, while compound 7c displayed 28.35 ± 1.01 µM HPA inhibition, 26.21 ± 1.17 µM HLAG inhibition, and 78.54 ± 0.54 % glucose uptake. Mechanistic studies revealed a dose-dependent increase in PPAR-γ transcription factor expression, supported by molecular docking that showed favorable interactions with key residues TYR473, SER289, and HIE323. Molecular dynamics simulations confirmed the stability of these interactions, and MM/GBSA binding free energy calculations indicated potential for further optimization. In vivo studies in STZ-induced diabetic Wistar rats demonstrated significant improvements in glucose homeostasis, Insulin sensitivity, and lipid metabolism, with a notable decrease in triglycerides and VLDL levels. Compound 7c also showed an improved pharmacokinetic profile with a half-life of 4.01 h and an elimination rate constant of 0.325, compared to compound 7b. Both compounds enhanced glycogen content and antioxidant biomarkers, with a high safety profile (LD₅₀ of 500 mg/kg). Overall, compound 7c stands out as a promising lead for further development, with compound 7b also showing strong potential, providing valuable insights for future antidiabetic drug development efforts.

Density Functional Theory; E-pharmacophore modeling; PPAR-γ TF expression; Thiazolidine-2,4-dione.