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Abstract
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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.
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