Development of 3,5-dinitrobenzoate-based 5-lipoxygenase inhibitors

Bioorg Med Chem. 2014 Apr 15;22(8):2396-402. doi: 10.1016/j.bmc.2014.03.008. Epub 2014 Mar 17.

Abstract

Human 5-lipoxygenase (5-LOX) is a well-validated target for anti-inflammatory therapy. Development of novel 5-LOX inhibitors with higher activities is highly demanded. In previous study, we have built a model for the active conformation of human 5-LOX, and identified naphthalen-1-yl 3,5-dinitrobenzoate (JMC-4) as a 5-LOX inhibitor by virtual screening. In the present work, 3,5-dinitrobenzoate-based 5-lipoxygenase inhibitors were developed. Twenty aryl 3,5-dinitrobenzoates, N-aryl 3,5-dinitrobenzamides and analogues were designed and synthesized. Several of them were found with significantly increased activities according to cell-free assay and human whole blood assay. The structure-activity relationship study may provide useful insights for designing effective 5-LOX inhibitors.

Keywords: 3,5-Dinitrobenzoate; 5-Lipoxygenase inhibitors; Cell-free assay; Human whole blood assay; SAR study.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents / chemical synthesis
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / metabolism
  • Arachidonate 5-Lipoxygenase / chemistry*
  • Arachidonate 5-Lipoxygenase / metabolism
  • Binding Sites
  • Humans
  • Lipoxygenase Inhibitors / chemical synthesis
  • Lipoxygenase Inhibitors / chemistry*
  • Lipoxygenase Inhibitors / metabolism
  • Molecular Docking Simulation
  • Nitrobenzoates / chemical synthesis
  • Nitrobenzoates / chemistry*
  • Nitrobenzoates / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • Lipoxygenase Inhibitors
  • Nitrobenzoates
  • 3,5-dinitrobenzoic acid
  • Arachidonate 5-Lipoxygenase