Discovery of 3-(4-bromophenyl)-6-nitrobenzo[1.3.2]dithiazolium ylide 1,1-dioxide as a novel dual cyclooxygenase/5-lipoxygenase inhibitor that also inhibits tumor necrosis factor-alpha production

Bioorg Med Chem. 2010 Jan 15;18(2):597-604. doi: 10.1016/j.bmc.2009.12.008. Epub 2009 Dec 6.

Abstract

In the present study we have discovered compound 1, a benzo[1.3.2]dithiazolium ylide-based compound, as a new prototype dual inhibitor of cyclooxygenase (COX) and 5-lipoxygenase (5-LOX). Compound 1 was initially discovered as a COX-2 inhibitor, resulting indirectly from the COX-2 structure-based virtual screening that identified compound 2 as a virtual hit. Compounds 1 and 2 inhibited COX-1 and COX-2 in mouse macrophages with IC(50) in the range of 1.5-18.1microM. Both compounds 1 and 2 were also found to be potent inhibitors of human 5-LOX (IC(50)=1.22 and 0.47microM, respectively). Interestingly, compound 1 also had an inhibitory effect on tumor necrosis factor-alpha (TNF-alpha) production (IC(50)=0.44microM), which was not observed with compound 2. Docking studies suggested the (S)-enantiomer of 1 as the biologically active isomer that binds to COX-2. Being a cytokine-suppressive dual COX/5-LOX inhibitor, compound 1 may represent a useful lead structure for the development of advantageous new anti-inflammatory agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzothiazoles
  • Cell Line
  • Crystallography, X-Ray
  • Cyclic S-Oxides
  • Cyclooxygenase 1 / metabolism*
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase Inhibitors / chemical synthesis
  • Cyclooxygenase Inhibitors / chemistry
  • Cyclooxygenase Inhibitors / pharmacology*
  • Drug Discovery
  • Humans
  • Lipoxygenase Inhibitors* / chemical synthesis
  • Lipoxygenase Inhibitors* / chemistry
  • Lipoxygenase Inhibitors* / pharmacology*
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Nitro Compounds / chemical synthesis
  • Nitro Compounds / chemistry
  • Nitro Compounds / pharmacology*
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • 3-(4-bromophenyl)-6-nitrobenzo(1.3.2)dithiazolium ylide 1,1-dioxide
  • Benzothiazoles
  • Cyclic S-Oxides
  • Cyclooxygenase Inhibitors
  • Lipoxygenase Inhibitors
  • Nitro Compounds
  • Thiazoles
  • Tumor Necrosis Factor-alpha
  • Cyclooxygenase 1
  • Cyclooxygenase 2