title: Release of nitrite from the antitubercular nitroimidazole drug PA-824 and analogues upon one-electron reduction in protic, non-aqueous solvent.
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.
authors.affiliation: Department of Chemistry, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
authors.forename: Andrej
authors.initials: A
authors.lastname: Maroz
authors.forename: Sujata S
authors.initials: SS
authors.lastname: Shinde
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Ma
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: Brian D
authors.initials: BD
authors.lastname: Palmer
authors.forename: Robert F
authors.initials: RF
authors.lastname: Anderson
mesh_terms: D000332:Aerobiosis; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D004579:Electron Transport; D000860:Hypoxia; D013058:Mass Spectrometry; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009570:Nitriles / Q000737:chemistry; D009573:Nitrites / Q000737:chemistry*; D009578:Nitrobenzenes / Q000737:chemistry; D009593:Nitroimidazoles / Q000737:chemistry* / Q000494:pharmacology; D011675:Pulse Radiolysis; D026361:Reactive Nitrogen Species; D012997:Solvents / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D014867:Water / Q000737:chemistry
chemical_list: D000995:Antitubercular Agents; D009570:Nitriles; D009573:Nitrites; D009578:Nitrobenzenes; D009593:Nitroimidazoles; D026361:Reactive Nitrogen Species; D012997:Solvents; C410767:pretomanid; D014867:Water; C072353:4-nitrobenzonitrile