In this article, we report novel leukotriene (LT) biosynthesis inhibitors that may target 5-lipoxygenaseactivating 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 ¼ 0.24 mM, each) seemingly by targeting FLAP with weak inhibition on 5-LO (IC50 8 mM). 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.

4,5-Diarylisoxazol-3-carboxylic acids: A new class of leukotriene biosynthesis inhibitors potentially targeting 5-lipoxygenase-activating protein (FLAP)

CAROTTI, Andrea;MACCHIARULO, Antonio;
2016-01-01

Abstract

In this article, we report novel leukotriene (LT) biosynthesis inhibitors that may target 5-lipoxygenaseactivating 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 ¼ 0.24 mM, each) seemingly by targeting FLAP with weak inhibition on 5-LO (IC50 8 mM). 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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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/1382526
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