Discovery of 2-Substituted 3-Arylquinoline Derivatives as Potential Anti-Inflammatory Agents Through Inhibition of LPS-Induced Inflammatory Responses in Macrophages

Abstract

We describe herein the preparation of certain 2-substituted 3-arylquinoline derivatives and the evaluation of their anti-inflammatory effects in LPS-activated murine J774A.1 macrophage cells. Among these newly synthesized 2-substituted 3-arylquinoline derivatives, 2-(4-methoxy- benzoyl)-3-(3,4,5-trimethoxyphenyl)quinoline (18a) and 2-(4-fluorobenzoyl)-3-(3,4,5-trimethoxy- phenyl)quinoline (18b) are two of the most active compounds which can inhibit the production of NO at non-cytotoxic concentrations. Our results have also indicated that compounds 18a and 18b significantly decrease the secretion of pro-inflammatory cytokines (TNF-á and IL-6), inhibit the expression of iNOS, suppress the phosphorylation of MAPKs, and attenuate the activity of NF-êB by LPS-activated macrophages. Through molecular docking analysis, we found that 18b could fit into the middle of the TNF-á dimer and form hydrophobic interactions with Leu55, Leu57 chain A and B, Tyr59, Val123 chain B and D, Ile 155. These results suggest that both 18a and 18b are potential lead compounds in inhibiting LPS-induced inflammatory responses. Further structural optimization to discover novel anti-inflammatory agents is ongoing.

Small molecule compounds with good anti-inflammatory activity reported in the literature from 01/2009 to 05/2021: a review

“…Among the compounds, 63a and 63b ( Figure 8 ) were the most active and they could inhibit production of NO at non-cytotoxic concentrations. Moreover, the two compounds had significant anti-inflammatory activities on LPS-activated macrophages through inhibiting production of NO, TNF-α, and IL-6, attenuating the activity of NF-êB, repressing iNOS expression, and suppressing phosphorylation of MAPKs 78 .…”

Hepatoprotective Activity of Leptadenia hastata (Asclepiadaceae) on Acetaminophen-Induced Toxicity in Mice: In Vivo Study and Characterization of Bioactive Compounds through Molecular Docking Approaches

“…This interaction is favored by the formation of hydrogen bonds with Ala 275, Tyr 284, and NAG 404 residues and hydrophobic bonds with Asn 161, Trp 220, Arg 274, Ala 275, Tyr 276, Tyr 284, and NAG 404 residues. Previous studies showed that some quinoline derivatives with anti-inflammatory properties might form a stable complex with TNF α by docking in the middle pocket of dimers [ 36 ]⁠. However, no hydrogen bond was observed in these studies which could be explained by the different nature of the docked molecule and the docking approach.…”

Discovery of 4-Anilinoquinolinylchalcone Derivatives as Potential NRF2 Activators

“…Orange solid; yield: 70%; Mp. 139.8-140.2 °C ([ 22 ], lit: 138.1-139.2 °C); 1 H-NMR (CDCl 3 ) δ 10.18 (s, 1H, CHO), 8.32-8.26 (m, 2H), 8.09 (s, 1H, 3-H), 7.91-7.87 (m, 1H), 7.82-7.77 (m, 1H); 13 C-NMR (CDCl 3 ) δ 192.56, 152.34, 148.67, 144.20, 131.30, 130.85, 130.19, 128.05, 124.41, 117.57.…”

“…Recently, we have synthesized certain 2-substituted 3-arylquinoline derivatives and the evaluation of their anti-inflammatory effects in LPS-activated murine macrophage cell line J774A.1 cells. 2-(4-Fluoro-benzoyl)-3-(3,4,5-trimethoxyphenyl)quinoline significantly decreases the secretion of pro-inflammatory cytokines (TNF-α and IL-6) in the LPS-activated macrophages [ 22 ]. The present report describes the synthesis of novel hybrid molecules, which bears both quinoline and chalcone moieties and evaluate for their NRF2 activating activities.…”