4.7 Article

Synthesis and bio-evaluation of human macrophage migration inhibitory factor inhibitor to develop anti-inflammatory agent

Journal

BIOORGANIC & MEDICINAL CHEMISTRY
Volume 19, Issue 24, Pages 7365-7373

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2011.10.056

Keywords

Human macrophage migration inhibitory factor (huMIF) inhibitor; Tautomerase activity; Nuclear factor kappa-B (NF-kappa B); Nitric oxide synthase; Nitric oxide; Inflammation

Funding

  1. Council of Scientific and Industrial Research (CSIR) New Delhi
  2. University Grants Commission (UGC) New Delhi
  3. University of Burdwan
  4. Department of Science and Technology (DST)

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Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, is involved in the development of an array of inflammatory disorders including rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis and sepsis. The synthesis of MIF-inhibitor is a rationale approach to develop novel anti-inflammatory agent to treat multitude of inflammatory diseases. In this work, we have synthesized and evaluated MIF-inhibitory activity of a series of small molecules containing isoxazoline skeleton. Mode of binding of this inhibitor to human MIF (huMIF) was determined by docking studies. The synthesized molecules inhibit tautomerase activity of huMIF. The anti-inflammatory activity of the most active inhibitor, 4-((3-(4-hydroxy-3-methoxyphenyl)-4, 5-dihydroisoxazol-5-yl) methoxy) benzaldehyde (4b) was evaluated against huMIF-induced inflammation in a cellular model (RAW 264.7 cell). Compound 4b significantly inhibits huMIF-mediated NF-kappa B translocation to the nucleus, up-regulation of inducible nitric oxide synthase and nitric oxide production in RAW 264.7 cell which are the markers for inflammation. The compound 4b is not cytotoxic as evident from cell viability assay. Hence, the compound 4b has potential to be a novel anti-inflammatory agent. (C) 2011 Elsevier Ltd. All rights reserved.

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