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Issue 8, 2018
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Synthesis and evaluation of 6-heteroarylamino-2,4,5-trimethylpyridin-3-ols as inhibitors of TNF-α-induced cell adhesion and inflammatory bowel disease

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Abstract

Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal tract with complex pathogenesis. Here, we synthesized 6-heteroarylamino analogues to inhibit TNF-α-induced adhesion of monocytes to colon epithelial cells which are implicated in the initial inflammation process of IBD. The best analogue, 16a, showed IC50 = 0.29 μM, which is about five orders of magnitude better than that of 5-aminosalicylic acid (5-ASA), a positive control. Oral administration of 6f and 16a dramatically ameliorated 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colon inflammation in rat. The ameliorating effects were accompanied by a high level of recovery in colon and body weights and in the myeloperoxidase (MPO) level. Consistently, the compounds suppressed the expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein 1 (MCP-1). Moreover, they significantly suppressed the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 while increasing the level of IL-10, an anti-inflammatory cytokine.

Graphical abstract: Synthesis and evaluation of 6-heteroarylamino-2,4,5-trimethylpyridin-3-ols as inhibitors of TNF-α-induced cell adhesion and inflammatory bowel disease

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Publication details

The article was received on 21 Mar 2018, accepted on 02 Jun 2018 and first published on 08 Jun 2018


Article type: Research Article
DOI: 10.1039/C8MD00156A
Citation: Med. Chem. Commun., 2018,9, 1305-1310
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    Synthesis and evaluation of 6-heteroarylamino-2,4,5-trimethylpyridin-3-ols as inhibitors of TNF-α-induced cell adhesion and inflammatory bowel disease

    S. W. Park, S. Banskota, P. Gurung, Y. J. Jin, H. Kang, C. L. Chaudhary, S. Y. Lee, B. Jeong, J. Kim and T. Nam, Med. Chem. Commun., 2018, 9, 1305
    DOI: 10.1039/C8MD00156A

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