Further studies on ethyl 5-hydroxy-indole-3-carboxylate scaffold: design, synthesis and evaluation of 2-phenylthiomethyl-indole derivatives as efficient inhibitors of human 5-lipoxygenase

Eur J Med Chem. 2014 Jun 23:81:492-8. doi: 10.1016/j.ejmech.2014.05.033. Epub 2014 May 14.

Abstract

5-Lipoxygenase (5-LO), an enzyme that catalyzes the initial steps in the biosynthesis of pro-inflammatory leukotrienes, is an attractive drug target for the pharmacotherapy of inflammatory and allergic diseases. Here, we present the design, synthesis and biological evaluation of novel series of ethyl 5-hydroxyindole-3-carboxylate derivatives that efficiently inhibit human 5-LO. SAR analysis revealed that the potency of compounds is closely related to the positioning of the substituents at the phenylthiomethyl ring. The introduction of methyl or chlorine groups in ortho- and ortho/para-position of thiophenol represent the most favorable modifications. Among all tested compounds, ethyl 5-hydroxy-2-(mesitylthiomethyl)-1-methyl-1H-indole-3-carboxylate (19) is the most potent derivative which blocks 5-LO activity in cell-free assays with IC50 = 0.7 μM, and suppressed 5-LO product synthesis in polymorphonuclear leukocytes with IC50 = 0.23 μM.

Keywords: 5-Lipoxygenase; Indoles; Leukotriene.

MeSH terms

  • Arachidonate 5-Lipoxygenase / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Lipoxygenase Inhibitors / chemical synthesis
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology*
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • 2-phenylthiomethyl-indole
  • Indoles
  • Lipoxygenase Inhibitors
  • Arachidonate 5-Lipoxygenase