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

• Main Authors: Cheng-Yao Yang, Yung-Li Hung, Kai-Wei Tang, Shu-Chi Wang, Chih-Hua Tseng, Cherng-Chyi Tzeng, Po-Len Liu, Chia-Yang Li, Yeh-Long Chen
• Format: Article
• Language: English
• Published: MDPI AG 2019-03-01
• Series: Molecules
• Subjects: anti-inflammatory agents; arylquinoline derivatives; nitric oxide (NO); tumor necrosis factor-á (TNF-á); interleukin-6 (IL-6)
• Online Access: https://www.mdpi.com/1420-3049/24/6/1162
• 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 (<b>18a</b>) and 2-(4-fluorobenzoyl)-3-(3,4,5-trimethoxy- phenyl)quinoline (<b>18b</b>) 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 <b>18a</b> and <b>18b</b> significantly decrease the secretion of pro-inflammatory cytokines (TNF-&#225; and IL-6), inhibit the expression of iNOS, suppress the phosphorylation of MAPKs, and attenuate the activity of NF-&#234;B by LPS-activated macrophages. Through molecular docking analysis, we found that <b>18b</b> could fit into the middle of the TNF-&#225; 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 <b>18a</b> and <b>18b</b> are potential lead compounds in inhibiting LPS-induced inflammatory responses. Further structural optimization to discover novel anti-inflammatory agents is ongoing.