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

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.

Preliminary Insight of Pyrrolylated-Chalcones as New Anti-Methicillin-Resistant Staphylococcus aureus (Anti-MRSA) Agents

“…It is important to highlight that though many analogues of pyrrolylated-chalcones have been previously synthesized for various bioactivities [ 9 , 11 , 12 , 13 , 14 ], we would like to explore further the therapeutic uses of the synthesized chalcones particularly as anti-MRSA agents in this present study. Little has been reported on the in-depth anti-MRSA potential of pyrrolylated-chalcones thus far.…”

“…The known pyrrolylated-chalcones ( 1 – 4 and 6 – 10 ) were synthesized following the method as described by Mohd Faudzi et al (2020) [ 9 ]. The general and spectrometry data, including the percentage yield and melting point, of the synthesized molecules 1 – 15 was tabulated in Table S1 of Supplementary Materials .…”

“…The organic layer was collected, dried with anhydrous MgSO 4 , and evaporated under reduced pressure. The crude products were purified by column chromatography and/or recrystallization techniques to yield pure compounds [ 9 ]. The chemical characterization was only discussed for the newly synthesized molecules.…”

“…In this present study, a series of non-associated pan-assay interference compounds (PAINS) (see Supplementary Materials), the pyrrolylated-chalcones, including new analogues 5 and 11-15 were synthesized via Claisen-Schmidt condensation by reacting 2acetylpyrrole with the appropriate fluoro-, nitro-, and hydroxyl-containing benzaldehydes in ethanolic sodium hydroxide for 24 h at room temperature (Scheme 1) [9]. All the As a continuation of our endeavors towards the exploration of the therapeutic potential of pyrrolylated-chalcones as new anti-MRSA hit-candidates, we herein evaluate the anti-MRSA properties of the pyrrolylated-chalcones (1-15) using in vitro disc diffusion, MIC, MBC, time-kill, and SEM analyses.…”

“…In this present study, a series of non-associated pan-assay interference compounds (PAINS) (see Supplementary Materials), the pyrrolylated-chalcones, including new analogues 5 and 11-15 were synthesized via Claisen-Schmidt condensation by reacting 2-acetylpyrrole with the appropriate fluoro-, nitro-, and hydroxyl-containing benzaldehydes in ethanolic sodium hydroxide for 24 h at room temperature (Scheme 1) [9]. All the synthesized compounds were purified by gravitational column chromatography and recrystallization techniques, followed by structural elucidation via spectroscopic analyses, including 1 H-, 13 C-, and 19 F-NMR, Fourier transform infra-red (FT-IR), and direct infusion-mass spectrometry (DI-MS), as well as high-resolution mass spectrometry (HRMS) for new molecules.…”