In Silico Design, Synthesis and Evaluation of Novel Series of Benzothiazole- Based Pyrazolidinediones as Potent Hypoglycemic Agents

Abstract

Background: The discovery of novel ligand binding domain (LBD) of peroxisome pro-liferator-activated receptor γ (PPARγ) has recently attracted attention to few research groups in order to develop more potent and safer antidiabetic agents. Objective: This study is focused on docking-based design and synthesis of novel compounds combining benzothiazole and pyrazolidinedione scaffold as potential antidiabetic agents. Methods: Several benzothiazole-pyrazolidinedione hybrids were synthesized and tested for their in vivo anti-hyperglycemic activity. Interactions profile of title compounds against PPARγ was exam-ined through molecular modelling approach. Results: All tested compounds exhibited anti-hyperglycemic activity similar or superior to the reference drug Rosiglitazone. Introducing chlorine atom and alkyl group at position-6 and-5 respectively on benzothiazole core resulted in enhancing the anti-hyperglycemic effect. Docking study revealed that such groups demonstrated favorable hydrophobic interactions with novel LBD Ω-pocket of PPARγ protein. Conclusion: Among the tested compounds, N-(6-chloro-5-methylbenzo[d]thiazol-2-yl-4-(4((3,5-dioxopyrazolidin-4-ylidene)methyl)phenoxy)butanamide 5b was found to be the most potent compound and provided valuable insights to further develop novel hybrids as anti-hyperglycemic agents. © 2020 Elsevier B.V., All rights reserved.