JAC Advance Access published online on May 23, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn214
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Original research |
In vitro and in vivo antimycobacterial activities of ketone and amide derivatives of quinoxaline 1,4-di-N-oxide
1 Unidad en Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada (CIFA), Universidad de Navarra, C/Irunlarrea s/n, 31080 Pamplona, Spain 2 Southern Research Institute, Birmingham, AL 35225-53053, USA 3 Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA 4 Institute for Tuberculosis Research, University of Illinois at Chicago, IL 60612, USA 5 Division of AIDS, National Institute of Allergy and Infectious Diseases, Therapeutics Research Program, Bethesda, MD 20892, USA
Received 16 January 2008; returned 25 March 2008; revised 18 April 2008; accepted 25 April 2008
* Corresponding author. Tel: +1-301-496-8424; Fax: +1-301-451-5481; E-mail: rgoldman{at}niaid.nih.gov
Objectives: 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 
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.
Key Words: antitubercular drugs , resistance , in vivo efficacy