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Synthesis and bio-evaluation of human macrophage migration inhibitory factor inhibitor to develop anti-inflammatory
Athar Alam1, Chinmay Pal, Manish Goyal
1Department of Infectious Diseases and Immunology, Indian Institute of Chemical Biology, 4 Raja S C Mullick Road, Jadavpur, Kolkata 700 032, West Bengal, India.
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.
Insights
Researchers developed novel isoxazoline-based small molecules that inhibit macrophage migration inhibitory factor (MIF). The lead compound, 4b, demonstrates significant anti-inflammatory effects in cellular models, showing potential as a new therapeutic agent.
Area of Science:
- Medicinal Chemistry
- Immunology
- Pharmacology
Background:
- Macrophage migration inhibitory factor (MIF) is a key pro-inflammatory cytokine implicated in various autoimmune and inflammatory diseases.
- Developing inhibitors of MIF is a promising strategy for novel anti-inflammatory drug discovery.
Purpose of the Study:
- To synthesize and evaluate isoxazoline derivatives for their MIF-inhibitory and anti-inflammatory activities.
- To identify potent MIF inhibitors with therapeutic potential for inflammatory conditions.
Main Methods:
- Synthesis of a series of isoxazoline-containing small molecules.
- In vitro evaluation of MIF tautomerase inhibition and anti-inflammatory effects in RAW 264.7 cells.
- Docking studies to elucidate the binding mode of inhibitors to human MIF (huMIF).
Main Results:
- Several synthesized isoxazoline derivatives exhibited MIF inhibitory activity.
- Compound 4b, 4-((3-(4-hydroxy-3-methoxyphenyl)-4, 5-dihydroisoxazol-5-yl) methoxy) benzaldehyde, showed potent anti-inflammatory effects.
- Compound 4b effectively inhibited huMIF-induced NF-κB nuclear translocation, iNOS upregulation, and nitric oxide production without cytotoxicity.
Conclusions:
- The isoxazoline scaffold is effective for developing MIF inhibitors.
- Compound 4b is a promising non-cytotoxic anti-inflammatory agent with potential for treating MIF-driven inflammatory diseases.
