Synthesis, molecular docking, and pharmacological evaluation of ۵-(۴-(۲-(۵-ethyl pyridine-۲-yl) ethoxy) benzyl)-۳-(phenylsulfonyl) thiazolidine-۲, ۴-dione against HFD-induced diabesity via interaction with the CB۱ receptor

Objective(s): CB۱ antagonism arbitrates a dormant shape to the endocannabinoid system that alleviates diverse pathological incidents of diabesity. The present study pursued the synthesis and evaluation of thiazolidine derivative (BAC) having pleiotropic action on CB۱R, with or without AM۲۵۱ (selective antagonist of the CB۱ receptor) against high-fat diet (HFD) induced diabesity in C۵۷BL/۶ mice. Materials and Methods: A molecular docking study for CB۱ antagonistic potential was conducted by Maestro ۱۱.۴ program (Schrodinger Inc., USA), and the thiazolidine derivative BAC was synthesized. The assessment of varied parameters including anthropometric, neurobehavioral, hyperglycemia, dyslipidemia, oxidative stress, and inflammatory cytokines was evaluated in HFD-fed animals as compared with individual and combined treatments of BAC and AM۲۵۱. Results: Incomparable to AM۲۵۱, the treatment of BAC was reported for a significant reduction in food intake and obesity, diabetic biomarkers, lipid profile, oxidative stress, and proinflammatory cytokine release. Moreover, the BAC treatment showed no significant alteration in neurobehavioral activity, including anxiety and depression. Conclusion: The preliminary in silico study suggests that BAC has a close interaction with CB۱ antagonism but has no sign of neurobehavioral alteration. Simultaneously, this compound showed significant ability to ameliorate diversity by the underlying mechanisms of minimizing oxidative stress, regularizing the lipid profile, and reducing pro-inflammatory cytokines.