Nitroimidazopyrazinones with Oral Activity against Tuberculosis and Chagas Disease in Mouse Models of Infection.
Ang CW, Lee BM, Jackson CJ, Wang Y, Franzblau SG, Francisco AF, Kelly JM, Bernhardt PV, Tan L, West NP, Sykes ML, Hinton AO, Bolisetti R, Avery VM, Cooper MA, Blaskovich MAT.
Tuberculosis and parasitic infections continue to impose a significant threat to global public health and economic growth. There is an urgent need to develop new treatments to combat these diseases. Here, we report the <i>in vitro</i> and <i>in vivo</i> profiles of a new bicyclic nitroimidazole subclass, namely, nitroimidazopyrazinones, against mycobacteria and <i>Trypanosoma cruzi</i>. Derivatives with monocyclic side chains were selective against <i>Mycobacterium tuberculosis</i> and were able to reduce the bacterial load when dosed orally in mice. We demonstrated that deazaflavin-dependent nitroreductase (Ddn) could act effectively on nitroimidazopyrazinones, indicating the potential of Ddn as an activating enzyme for these new compounds in <i>M. tuberculosis</i>. Oral administration of compounds with extended biaryl side chains (<b>73</b> and <b>74</b>) was effective in suppressing infection in an acute <i>T. cruzi</i>-infected murine model. These findings demonstrate that active nitroimidazopyrazinones have potential to be developed as orally available clinical candidates against both tuberculosis and Chagas disease.