Isoniazid is the front-line treatment for infections by Mycobacterium tuberculosis.Unfortunately, despite its simple structure and over half-a-century of therapeutic use its mechanism of action remains complex and unclear. Although complex there are several common features to the proposed mechanisms one of which is that isoniazid is a prodrug that once activated by the mycobacterial catalase-peroxidase KatG generates reactive intermediates that are responsible for its action. Electron spin resonance studies have indicated that these reactive intermediates are free radicals derived from isoniazid. However, the mechanism by which the free radicals are produced and their precise structure are still uncertain. While the mechanism of activation of isoniazid has been investigated using a variety of in vitro techniques very little is known about the basic free radical chemistry of this therapeutic. To begin to address this situation, we report here the reaction of the oxidizing hydroxyl radical and reducing hydrated electron with isoniazid using pulse radiolysis techniques. The studies have determined absolute reaction rate constants, transient radical spectra, and initial reaction sites and free-radicals produced for isoniazid under both oxidative and reductive conditions. In addition steady-state irradiations and EPR spin trapping experiments have examined the production of nitric oxide under various solution conditions by isoniazid.

Fundamental oxidation and reduction chemistry of isoniazid and its reactive intermediates

240th National Meeting (2010)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.