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

• Published in: Molecules Vol. 24; no. 6; p. 1162
• Main Authors: Yang, Cheng-Yao, Hung, Yung-Li, Tang, Kai-Wei, Wang, Shu-Chi, Tseng, Chih-Hua, Tzeng, Cherng-Chyi, Liu, Po-Len, Li, Chia-Yang, Chen, Yeh-Long
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23.03.2019; MDPI
• Subjects: Amino Acids; Amino Acids - chemistry; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; arylquinoline derivatives; Cell culture; Cytokines; Cytotoxicity; Diabetes; Humans; Hydrophobic and Hydrophilic Interactions; Inflammation; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - pathology; Inflammatory diseases; interleukin-6 (IL-6); Kinases; Lipopolysaccharides; Lipopolysaccharides - toxicity; Macrophages; Macrophages - drug effects; Macrophages - pathology; MAP Kinase Kinase 1; MAP Kinase Kinase 1 - chemistry; MAP Kinase Kinase 1 - genetics; Mice; Molecular Docking Simulation; Nitric Oxide; nitric oxide (NO); Nitric Oxide - metabolism; Organic chemistry; QD241-441; Quinolines; Quinolines - chemistry; Quinolines - pharmacology; Sepsis; Signal Transduction; Signal Transduction - drug effects; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor-alpha - chemistry; Tumor Necrosis Factor-alpha - genetics; Tumor necrosis factor-TNF; tumor necrosis factor-á (TNF-á); nitric oxide (NO); anti-inflammatory agents; arylquinoline derivatives; tumor necrosis factor-á (TNF-á); interleukin-6 (IL-6)
• DOI: 10.3390/molecules24061162
• ISSN: 1420-3049

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.