حسن حبیبی

Diabetes mellitus (DM), a global health crisis affecting over 830 million people, demands innovative therapeutic strategies to address the limitations of current treatments, including adverse effects like weight gain and cardiovascular risks. This study reports the design, synthesis, and evaluation of novel 5-arylidene thiazolidinedione (TZD) acetic acid 1,2-diol monoesters (2a–2p) as potential antidiabetic agents. The compounds were synthesized via a five-step route, starting with TZD core formation, Knoevenagel condensation with aryl aldehydes, Nalkylation, ester hydrolysis, and chemoselective epoxide ring-opening catalyzed by butyl methyl imidazolium silica sulfate ([BMIm]SS). In vivo antidiabetic activity was assessed in streptozotocin (STZ)-induced diabetic mice, with compound 2c emerging as a standout candidate, reducing blood glucose levels by 83% over four weeks without mortality, comparable to glibenclamide. Molecular docking revealed 2c’s strong binding affinity (􀀀 146.27 kcal/mol) to peroxisome proliferator-activated receptor gamma (PPAR-γ), facilitated by hydrogen bonds, π-sulfur interactions, and hydrophobic forces. Density functional theory (DFT) analyses highlighted 2c’s enhanced reactivity (HOMO-LUMO gap: 5.77 eV) and nucleophilic character relative to rosiglitazone. Pharmacokinetic profiling indicated favorable drug-likeness for most derivatives, with 2c exhibiting high human intestinal absorption (96.42%) and low blood-brain barrier permeability. Notably, 2c demonstrated superior thermodynamic stability (Gibbs free energy: 􀀀 1983.1 Hartree/particle) and softness (σ: 0.347 eV⁻¹), correlating with its biological efficacy. These findings underscore the potential of TZD-based 1,2-diol monoesters as longacting hypoglycemic agents, with 2c warranting further development for diabetes therapy.