کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1393803 | 1501103 | 2016 | 10 صفحه PDF | دانلود رایگان |
• Inhibition of leukotriene (LT) biosynthesis is a promising strategy for treatment of inflammatory diseases.
• A series of 4,5-diarylisoxazol-3-carboxylic acids was designed and synthesized.
• Derivatives 39 and 40 significantly suppressed the LT biosynthesis in activated human neutrophils.
In this article, we report novel leukotriene (LT) biosynthesis inhibitors that may target 5-lipoxygenase-activating protein (FLAP) based on the previously identified isoxazole derivative (8). The design and synthesis was directed towards a subset of 4,5-diaryl-isoxazole-3-carboxylic acid derivatives as LT biosynthesis inhibitors. Biological evaluation disclosed a new skeleton of potential anti-inflammatory agents, exemplified by 39 and 40, which potently inhibit cellular 5-LO product synthesis (IC50 = 0.24 μM, each) seemingly by targeting FLAP with weak inhibition on 5-LO (IC50 ≥ 8 μM). Docking studies and molecular dynamic simulations with 5-LO and FLAP provide valuable insights into potential binding modes of the inhibitors. Together, these diaryl-isoxazol-3-carboxylic acids may possess potential as leads for development of effective anti-inflammatory drugs through inhibition of LT biosynthesis.
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Journal: European Journal of Medicinal Chemistry - Volume 113, 4 May 2016, Pages 1–10