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Inhibition of nitric oxide and prostaglandin E2 production by pyrrolylated-chalcones: synthesis, biological activity, crystal structure analysis, and molecular docking studies


Citation

Mohd Faudzi, Siti Munirah and Abdullah, Maryam Aisyah and Abdull Manap, Mohd Rashidi and Ismail, Ahmad Zaidi and Rullah, Kamal and Mohd Aluwi, Mohd Fadhlizil Fasihi and Ramli, Aizi Nor Mazila and Abas, Faridah and Lajis, Nordin (2020) Inhibition of nitric oxide and prostaglandin E2 production by pyrrolylated-chalcones: synthesis, biological activity, crystal structure analysis, and molecular docking studies. Bioorganic Chemistry, 94. art. no. 103376. pp. 1-12. ISSN 0045-2068; ESSN: 1090-2120

Abstract

In search of potent anti-inflammatory agents, twenty-four chalcone derivatives including seven new compounds (13 – 17, 21 and 23) containing pyrrole moiety were designed, synthesized, and assessed for their nitric oxide (NO) and prostaglandin E2 (PGE2) suppression ability on IFN-γ/LPS-induced RAW 264.7 macrophage cells. Results showed that none of the synthesized compounds were PAINS-associated molecules, with 3-(2,5-dimethoxyphenyl)-1-(1H-pyrrol-2-yl)-prop-2-en-1-one (compound 16) exhibiting remarkable inhibition activity towards PGE2 and NO production with IC50 values of 0.5 ± 1.5 µM and 12.1 ± 1.5 µM, respectively. Physicochemical and ADMET studies showed that majority of the compounds obey to Lipinski's rule of five (RO5) having high blood brain barrier (BBB) penetration, human intestinal absorption (HIA), P- glycoprotein (PgP) inhibition and plasma binding protein (PPB) inhibition. The obtained atomic coordinates for the single-crystal XRD of 16 were then applied in a molecular docking simulation, and compound 16 was found to participate in a number of important binding interactions in the binding sites of ERK and mPGES-1. Based on these results, we have observed the potential of compound 16 as a new hit anti-inflammatory agent, and these findings could serve as a basis for further studies on its mechanism of action.


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Additional Metadata

Item Type: Article
Divisions: Faculty of Food Science and Technology
Faculty of Science
Institute of Bioscience
DOI Number: https://doi.org/10.1016/j.bioorg.2019.103376
Publisher: Elsevier
Keywords: Inflammation; Leukocytes; Physicochemical; Nitric acid
Depositing User: Ms. Nuraida Ibrahim
Date Deposited: 19 Aug 2021 22:58
Last Modified: 19 Aug 2021 22:58
Altmetrics: http://www.altmetric.com/details.php?domain=psasir.upm.edu.my&doi=10.1016/j.bioorg.2019.103376
URI: http://psasir.upm.edu.my/id/eprint/89396
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