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

Author(s): Michelyne Haroun*

Journal Name: Medicinal Chemistry

Volume 16 , Issue 6 , 2020


DOI : 10.2174/1573406416666191227113716

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Graphical Abstract:


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.

Keywords: Benzothiazole, pyrazolidinedione, PPARγ inhibitor, Ω-pocket binding domain, In silico evaluation, Antihyperglycemic activity.

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VOLUME: 16
ISSUE: 6
Year: 2020
Published on: 06 September, 2020
Page: [812 - 825]
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DOI: 10.2174/1573406416666191227113716
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