Synthesis, molecular docking, and pharmacological evaluation of 5-(4-(2-(5-ethyl pyridine-2-yl) ethoxy) benzyl)-3-(phenylsulfonyl) thiazolidine-2, 4-dione against HFD-induced diabesity via interaction with the CB1 receptor

Abstract

Objective(s): CB1 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 CB1R, with or without AM251 (selective antagonist of the CB1 receptor) against high-fat diet (HFD) induced diabesity in C57BL/6 mice. Materials and Methods: A molecular docking study for CB1 antagonistic potential was conducted by Maestro 11.4 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 AM251. Results: Incomparable to AM251, 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 CB1 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.

Keywords

• cannabinoid receptor
• diabesity
• diabetes mellitus
• endocannabinoid
• obesity
• molecular docking