Hassan Habibi

This paper presents the design, synthesis, characterization, assessment of antidiabetic activity, and in silico studies of novel thiazolidinedione-morpholine hybrid ionic liquids. We successfully synthesized sixteen ionic liquids through a five-step synthetic process, subsequently screening their antidiabetic effects in streptozotocin- induced diabetic male Balb/C mice. Among these compounds, seven and five salts demonstrated significant antidiabetic activity after 2 and 4 weeks, respectively, compared to the reference drug glibenclamide, indicating their long-term efficacy. Notably, the compound 11 k as the most potent compound exhibited a consistent reduction in blood glucose levels throughout the study. Docking analysis of 11 k was performed using Molegro Virtual Docker (MVD 6.0), yielding ΔG values of 140.61 kcal/mol for rosiglitazone and 170.69 kcal/mol for 11 k. Molecular docking reveals that rosiglitazone lacks electrostatic interactions with the PPAR-γ enzyme’s active site, while 11 k enhances binding affinity through electrostatic interactions. Additionally, 11 k has double the total hydrogen bond energy of rosiglitazone. These findings indicate that both hydrogen bonds and elec- trostatic interactions are vital for stabilizing the ligand in the PPAR-γ active site and potentially improving its antidiabetic activity. Additionally, in silico analysis of pharmacokinetic and physicochemical properties confirmed that all synthesized salts complied with Lipinski’s rule of five.