title: The nitroimidazooxazines (PA-824 and analogs): structure-activity relationship and mechanistic studies.
abstract: PA-824 is an experimental anti-tubercular agent that has a novel mechanism of action. It is effective against both active and persistent forms of the disease and has recently shown early bactericidal activity in a Phase II clinical trial. This review summarizes recent studies on the mode of action of PA-824 and outlines successful efforts to prepare more effective second-generation analogs. PA-824 displays unusual chemistry following both enzymatic and radiolytic reduction, which is clearly related to its activity as an anti-tubercular agent. The nitroreductase enzyme deazaflavin-dependent nitroreductase, reduces PA-824 with loss of the nitro group, generating reactive nitrogen species such as nitric oxide, which appear important in mediating the activity of the drug. Bioreductive drugs such as PA-824 hold the promise of shorter treatment regimens.
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. b.denny@auckland.ac.nz
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: Brian D
authors.initials: BD
authors.lastname: Palmer
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; C410767:pretomanid