Title:In Silico Design, Synthesis and Evaluation of Novel Series of Benzothiazole- Based Pyrazolidinediones as Potent Hypoglycemic Agents
VOLUME: 16 ISSUE: 6
Author(s):Michelyne Haroun*
Affiliation:Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982
Keywords:Benzothiazole, pyrazolidinedione, PPARγ inhibitor, Ω-pocket binding domain, In silico evaluation, Antihyperglycemic
activity.
Abstract:
Background: The discovery of novel ligand binding domain (LBD) of peroxisome proliferator-
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 examined
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.