title: Synthesis and bio-evaluation of human macrophage migration inhibitory factor inhibitor to develop anti-inflammatory agent.
abstract: 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-κB 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.
authors.affiliation: Department of Infectious Diseases and Immunology, Indian Institute of Chemical Biology, 4 Raja S C Mullick Road, Jadavpur, Kolkata 700 032, West Bengal, India.
authors.forename: Athar
authors.initials: A
authors.lastname: Alam
authors.forename: Chinmay
authors.initials: C
authors.lastname: Pal
authors.forename: Manish
authors.initials: M
authors.lastname: Goyal
authors.forename: Milan Kumar
authors.initials: MK
authors.lastname: Kundu
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.forename: Mohd Shameel
authors.initials: MS
authors.lastname: Iqbal
authors.forename: Sumanta
authors.initials: S
authors.lastname: Dey
authors.forename: Samik
authors.initials: S
authors.lastname: Bindu
authors.forename: Souvik
authors.initials: S
authors.lastname: Sarkar
authors.forename: Uttam
authors.initials: U
authors.lastname: Pal
authors.forename: Nakul C
authors.initials: NC
authors.lastname: Maiti
authors.forename: Susanta
authors.initials: S
authors.lastname: Adhikari
authors.forename: Uday
authors.initials: U
authors.lastname: Bandyopadhyay
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II