Organic & Biomolecular Chemistry 2010-01-21

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

Andrej Maroz, Sujata S Shinde, Scott G Franzblau, Zhenkun Ma, William A Denny, Brian D Palmer, Robert F Anderson

Index: Org. Biomol. Chem. 8(2) , 413-8, (2010)

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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.