title: In vitro and in vivo antimycobacterial activities of ketone and amide derivatives of quinoxaline 1,4-di-N-oxide.
abstract: OBJECTIVE
  To evaluate a novel series of quinoxaline 1,4-di-N-oxides for in vitro activity against Mycobacterium tuberculosis and for efficacy in a mouse model of tuberculosis (TB).
  
  
  METHODS
  Ketone and amide derivatives of quinoxaline 1,4-di-N-oxide were evaluated in in vitro and in vivo tests including: (i) activity against M. tuberculosis resistant to currently used antitubercular drugs including multidrug-resistant strains (MDR-TB resistant to isoniazid and rifampicin); (ii) activity against non-replicating persistent (NRP) bacteria; (iii) MBC; (iv) maximum tolerated dose, oral bioavailability and in vivo efficacy in mice; and (v) potential for cross-resistance with another bioreduced drug, PA-824.
  
  
  RESULTS
  Ten compounds were tested on single drug-resistant M. tuberculosis. In general, all compounds were active with ratios of MICs against resistant and non-resistant strains of <or=4.00. One compound, 5, was orally active in a murine model of TB, bactericidal, active against NRP bacteria and active on MDR-TB and poly drug-resistant clinical isolates (resistant to 3-5 antitubercular drugs).
  
  
  CONCLUSIONS
  Quinoxaline 1,4-di-N-oxides represent a new class of orally active antitubercular drugs. They are likely bioreduced to an active metabolite, but the pathway of bacterial activation was different from PA-824, a bioreducible nitroimidazole in clinical trials. Compound 5 was bactericidal and active on NRP organisms indicating that activation occurred in both growing and non-replicating bacteria leading to cell death. The presence of NRP bacteria is believed to be a major factor responsible for the prolonged nature of antitubercular therapy. If the bactericidal activity and activity on non-replicating bacteria in vitro translate to in vivo conditions, quinoxaline 1,4-di-N-oxides may offer a path to shortened therapy.
authors.affiliation: Unidad en Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada (CIFA), Universidad de Navarra, C/Irunlarrea s/n, 31080 Pamplona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Villar
authors.forename: Esther
authors.initials: E
authors.lastname: Vicente
authors.forename: Beatriz
authors.initials: B
authors.lastname: Solano
authors.forename: Silvia
authors.initials: S
authors.lastname: Pérez-Silanes
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aldana
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Maddry
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Lenaerts
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Cho
authors.forename: Antonio
authors.initials: A
authors.lastname: Monge
authors.forename: Robert C
authors.initials: RC
authors.lastname: Goldman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D051379:Mice; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011810:Quinoxalines / Q000378:metabolism / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D011810:Quinoxalines; C003282:quindoxin