Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents

• Published in: Journal of enzyme inhibition and medicinal chemistry 2020-01, Vol.35 (1), p.187-198
• Main Authors: Liu, Wandong, Hou, Caiyun, Li, Jiaming, Ma, Xiaodong, Zhang, Yanchun, Hu, Mengqi, Huang, Yuanzheng
• Format: Article
• Language: English
• Subjects: Animals; anti-inflammation; Anti-inflammatory agents; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; COXs; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Inflammation; Inflammatory diseases; Kinases; Lipopolysaccharides; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Male; MAP kinase; Mice; Mice, Inbred ICR; Molecular Structure; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB protein; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; p38α MAPK; Pharmaceutical sciences; Pharmacy; Phosphorylation; Polypharmacological agent; RAW 264.7 Cells; Research Paper; Signal transduction; Signal Transduction - drug effects; Structure-Activity Relationship; talmapimod analogues
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2019.1693703

Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n, the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lipopolysaccharides-induced (LPS-induced) expressions of iNOS and COX-2. As illustrated by the western blot analysis, 6n downregulated both the NF-κB signalling and p38 MAPK phosphorylation. Further enzymatic assay identified 6n as a potent inhibitor against both p38α MAPK (IC 50 =1.95 µM) and COX-2 (IC 50 =0.036 µM). By virtue of the concomitant inhibition of p38α MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-κB and MAPK-signalling pathways, 6n, a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug.