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

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 Mazila Ramli, Aizi Nor and Abas, Faridah and Lajis, Nordin H. (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. pp. 1-12. ISSN 0045-2068

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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.

Item Type:	Article (Journal)
Additional Information:	9020/77065
Subjects:	R Medicine > RS Pharmacy and materia medica > RS403 Materia Medica-Pharmaceutical Chemistry
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Pharmacy Kulliyyah of Pharmacy > Department of Pharmaceutical Chemistry
Depositing User:	Dr Kamal Rullah
Date Deposited:	12 Dec 2019 16:21
Last Modified:	12 Nov 2020 15:18
URI:	http://irep.iium.edu.my/id/eprint/77065

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