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The Efficacy of Quinoxaline-2-carboxylate 1,4-di-N-oxide Derivatives in Experimental Tuberculosis.

Antimicrobial agents and chemotherapy 2008 Jul 14; In press

Link to PubMed abstract

Vicente E E, Villar R R, Burguete A A, Solano B B, Pérez-Silanes S S, Aldana I I, Maddry J JA, Lenaerts A AJ, Franzblau S SG, Cho S SH, Monge A A, Goldman R RC

Unidad en Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada (CIFA), Universidad de Navarra, C/Irunlarrea s/n, 31080 Pamplona, Spain; National Institute of Allergy and Infectious Diseases, Division of AIDS,

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 was comparable to that of H37Rv, as was indicated by the ratios of MICs against resistant and non-resistant strains, supporting the premise that 1,4-di-N-oxide quinoxaline derivatives have a novel mode of action unrelated to the currently used anti-tubercular drugs. Specific derivatives were further evaluated in a series of in vivo assays including maximum tolerated dose, oral bioavailability, and efficacy in a low dose aerosol mouse model of tuberculosis. One compound, ethyl 7-chloro-3-methylquinoxaline-2-carboxylate 1,4-dioxide, was found 1) active in reducing CFU counts in both the lung and spleen of infected mice following oral administration, 2) active on PA-824 resistant Mycobacterium bovis, indicating that the pathway of bioreduction/activation is different from PA-824 (a bioreduced nitroimidazole that is in clinical trials), and 3) very active against non-replicating bacteria adapted to low oxygen. These data indicate that 1,4-di-N-oxide quinoxalines hold promise for the treatment of tuberculosis.

Keywords: Tuberculosis