title: Efficacy of quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives in experimental tuberculosis.
abstract: This study extends earlier reports regarding the in vitro efficacies of the 1,4-di-N-oxide quinoxaline derivatives against Mycobacterium tuberculosis and has led to the discovery of a derivative with in vivo efficacy in the mouse model of tuberculosis. Quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives were tested in vitro against a broad panel of single-drug-resistant M. tuberculosis strains. The susceptibilities of these strains to some compounds were comparable to those of strain H(37)Rv, as indicated by the ratios of MICs for resistant and nonresistant strains, supporting the premise that 1,4-di-N-oxide quinoxaline derivatives have a novel mode of action unrelated to those of the currently used antitubercular drugs. Specific derivatives were further evaluated in a series of in vivo assays, including evaluations of the maximum tolerated doses, the levels of oral bioavailability, and the efficacies in a low-dose aerosol model of tuberculosis in mice. One compound, ethyl 7-chloro-3-methylquinoxaline-2-carboxylate 1,4-dioxide, was found to be (i) active in reducing CFU counts in both the lungs and spleens of infected mice following oral administration, (ii) active against PA-824-resistant Mycobacterium bovis, indicating that the pathway of bioreduction/activation is different from that of PA-824 (a bioreduced nitroimidazole that is in clinical trials), and (iii) very active against nonreplicating bacteria adapted to low-oxygen conditions. These data indicate that 1,4-di-N-oxide quinoxalines hold promise for the treatment of tuberculosis.
authors.affiliation: Unidad en Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada, Universidad de Navarra, Irunlarrea, Pamplona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Vicente
authors.forename: Raquel
authors.initials: R
authors.lastname: Villar
authors.forename: Asunción
authors.initials: A
authors.lastname: Burguete
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: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D008168:Lung / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests / Q000592:standards; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000382:microbiology; D013329:Structure-Activity Relationship; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D003497:Cyclic N-Oxides; D011810:Quinoxalines