Release of nitrite from the antitubercular nitroimidazole drug PA-824 and analogues upon one-electron reduction in protic, non-aqueous solvent

Org Biomol Chem. 2010 Jan 21;8(2):413-8. doi: 10.1039/b915877d. Epub 2009 Nov 4.

Abstract

The one-electron reduction chemistry of the antituberculosis drug PA-824, together with a series of closely related compounds, has been investigated in irradiated anaerobic propan-2-ol solution. The protic solvent, of low dielectric constant, was chosen to mimic the environment of a water-restricting active site of a model protein, which is capable of reducing the compounds. Radiolytic reduction of the compounds containing electron donating substituents in the 2-position of the imidazole ring released nitrite, with compounds that are highly active against Mycobacterium tuberculosis exhibiting high yields of nitrite. The release of cytotoxic reactive nitrogen species through a one-electron pathway, by as yet unidentified proteins, may play a role in the activity of this class of compounds against TB. The described radiolytic quantification of nitrite release may have utility as a preliminary screening test for nitroaromatic candidate drugs against the disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aerobiosis
  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacology
  • Electron Transport
  • Hypoxia
  • Mass Spectrometry
  • Mycobacterium tuberculosis / drug effects
  • Nitriles / chemistry
  • Nitrites / chemistry*
  • Nitrobenzenes / chemistry
  • Nitroimidazoles / chemistry*
  • Nitroimidazoles / pharmacology
  • Pulse Radiolysis
  • Reactive Nitrogen Species
  • Solvents / chemistry*
  • Spectrophotometry, Ultraviolet
  • Water / chemistry

Substances

  • Antitubercular Agents
  • Nitriles
  • Nitrites
  • Nitrobenzenes
  • Nitroimidazoles
  • Reactive Nitrogen Species
  • Solvents
  • pretomanid
  • Water
  • 4-nitrobenzonitrile