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Antimicrobial Agents and Chemotherapy, September 2008, p. 3321-3326, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00379-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Efficacy of Quinoxaline-2-Carboxylate 1,4-Di-N-Oxide Derivatives in Experimental Tuberculosis {triangledown}

Esther Vicente,1 Raquel Villar,1 Asunción Burguete,1 Beatriz Solano,1 Silvia Pérez-Silanes,1* Ignacio Aldana,1 Joseph A. Maddry,3 Anne J. Lenaerts,4 Scott G. Franzblau,5 Sang-hyun Cho,5 Antonio Monge,1 and Robert C. Goldman2

Unidad en Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada (CIFA), Universidad de Navarra, C/ Irunlarrea s/n, 31080 Pamplona, Spain,1 Therapeutics Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892,2 Southern Research Institute, Birmingham, Alabama 35225-53053,3 Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523,4 Institute for Tuberculosis Research, University of Illinois at Chicago, Chicago, Illinois 606125

Received 20 March 2008/ Returned for modification 2 May 2008/ Accepted 8 July 2008

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 H37Rv, 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.

* Corresponding author. Mailing address: Unidad en Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada (CIFA), Universidad de Navarra, C/ Irunlarrea s/n, 31080 Pamplona, Spain. Phone: 34 948 425653. Fax: 34 948 425652. E-mail: sperez{at}unav.es

{triangledown} Published ahead of print on 14 July 2008.

Antimicrobial Agents and Chemotherapy, September 2008, p. 3321-3326, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00379-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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