In vitro and in vivo antimycobacterial activities of ketone and amide derivatives of quinoxaline 1,4-di-N-oxide

Abstract: 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

Efficacy of quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives in experimental tuberculosis

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

Efficacy of quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives in experimental tuberculosis

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