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Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents.

ABSTRACT: 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 (IC₅₀=1.95 µM) and COX-2 (IC₅₀=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.

SUBMITTER: Liu W

PROVIDER: S-EPMC6882468 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents.

Liu Wandong W Hou Caiyun C Li Jiaming J Ma Xiaodong X Zhang Yanchun Y Hu Mengqi M Huang Yuanzheng Y

Journal of enzyme inhibition and medicinal chemistry 20201201 1

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 phosphor ...[more]

PMID: 31752552

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