Nitroimidazopyrazinones with Oral Activity against Tuberculosis and Chagas Disease in Mouse Models of Infection

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 in vitro and in vivo profiles
of a new bicyclic nitroimidazole subclass, namely, nitroimidazopyrazinones,
against mycobacteria and Trypanosoma cruzi. Derivatives with monocyclic side chains were selective against Mycobacterium tuberculosis 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 M. tuberculosis. Oral administration of compounds with extended biaryl side chains
(73 and 74) was effective in suppressing
infection in an acute T. cruzi-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.