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

BANOĞLU E. , Celikoglu E., Voelker S., OLĞAÇ A. , Gerstmeier J., Garscha U., ...Daha Fazla

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, cilt.113, ss.1-10, 2016 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 113
  • Basım Tarihi: 2016
  • Doi Numarası: 10.1016/j.ejmech.2016.02.027
  • Sayfa Sayıları: ss.1-10


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 mu M, each) seemingly by targeting FLAP with weak inhibition on 5-LO (IC50 > 8 mu M). 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. (C) 2016 Elsevier Masson SAS. All rights reserved.