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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Design, Synthesis, Docking Studies, Enzyme Inhibitory and Antiplatelet Aggregation Activities of New 1,3-Diphenyl-3-(Phenylthio)Propan-1-One Derivatives as Selective COX-2 Inhibitors

Author(s): Maryam Bayanati, Bahram Daraei* and Afshin Zarghi*

Volume 23, Issue 2, 2023

Published on: 20 August, 2022

Page: [192 - 200] Pages: 9

DOI: 10.2174/1871520622666220609111628

Price: $65

Abstract

Background: Cancer is the second leading cause of death worldwide after heart disease. A vast number of studies indicated that selective cyclooxygenase-2 (COX-2) inhibitors could be chemopreventive against different types of cancer because the expression of COX-2 is increased. Therefore, to develop new therapeutics for cancer, the design and synthesis of new COX-2 inhibitors with few side effects seem attractive as anti-cancer agents.

Objective: Some of the well-known drugs that have been widely used for some time have been removed from the market due to the cardiac side effects they cause, so there is a need to introduce a scaffold that can inhibit COX-2 with high potency and low side effects. This study aimed to introduce a new COX-2 inhibitor structure.

Methods: A new series of β-aryl-β-mercapto ketones possessing a methylsulfonyl pharmacophore was synthesized and evaluated as selective COX-2 inhibitors. In-vitro COX-1 and COX-2 inhibition effects of these compounds were evaluated, and molecular modeling was examined. Also, the antiplatelet aggregation activity of the synthesized compounds was tested.

Results: In-vitro COX-1 and COX-2 inhibition assays indicated that almost all newly synthesized compounds showed selectivity for COX-2 with IC50 values in the 0.07-0.22 μM range and COX-2 selectivity indexes in the 170 to 703.7 range. Among the tested compounds 1-(4-(methylsulfonyl)phenyl)-3-phenyl-3-(phenylthio)propan-1-one (4a), 3-(3,4- dimethoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-3-(phenylthio)propan-1-one (4g) and 3-(4-fluorophenyl)-1-(4-(methyl sulfonyl)phenyl)-3-(phenylthio)propan-1-one (4h) were the most potent COX-2 inhibitors and 3-(3,4- dimethoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-3-(phenylthio)propan-1-one had the highest selectivity index for COX-2 enzyme inhibitory activity. The Anti-platelet aggregation activity results indicated that the compound 1-(4- (methylsulfonyl)phenyl)-3-(phenylthio)-3-(p-tolyl)propan-1-one (4b) possesses the strong anti-platelet activity. Our molecular modeling studies also indicated that the methylsulfonyl pharmacophore group is placed into the adjunct pocket in the COX-2 active site and forms hydrogen bond interactions with NH of Arg513 and NH of His90.

Conclusion: In brief, all designed and synthesized compounds showed moderate to good COX-2 inhibitory effects and showed good anti-platelet activity. Therefore, these compounds have the potential for further research into developing anti-cancer agents.

Keywords: COX-2 inhibitory, anti-platelet aggregation, docking study, aldol condensation, thio-Michael addition, β-aryl-β-mercapto ketones.

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