title: The effect of 5-substitution on the electrochemical behavior and antitubercular activity of PA-824.
abstract: Nitroimidazole PA-824 is part of an exciting new class of compounds currently undergoing clinical evaluation as novel TB therapeutics. The recently elucidated mechanism of action of PA-824 involves reduction of the nitroimidazole ring and subsequent nitric oxide release. The importance of this compound and its unique activity prompted us to explore how substitution of the nitroimidazole ring would affect electrochemical reduction and antitubercular activity. We prepared analogs of PA-824 with bromo, chloro, cyano, and amino substituents in the 5-position of the aromatic ring. We found that substitution of the imidazole ring greatly influences reduction and the stability of the corresponding nitro radical anion. Further, the antitubercular activities of the bromo and chloro analogs may indicate that an alternate nitroreductase pathway within Mycobacterium tuberculosis exists.
authors.affiliation: Bioelectrochemistry Laboratory, Chemical and Pharmaceutical Sciences Faculty, University of Chile, PO Box 233, Santiago 1, Chile.
authors.forename: Soledad
authors.initials: S
authors.lastname: Bollo
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Núñez-Vergara
authors.forename: Sunhee
authors.initials: S
authors.lastname: Kang
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Helena I
authors.initials: HI
authors.lastname: Boshoff
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.forename: Juan A
authors.initials: JA
authors.lastname: Squella
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Dowd
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D004563:Electrochemistry; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; C410767:pretomanid