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

Ang, Chee WeiORCID logo; Lee, Brendon M; Jackson, Colin JORCID logo; Wang, Yuehong; Franzblau, Scott GORCID logo; Francisco, Amanda FORCID logo; Kelly, John MORCID logo; Bernhardt, Paul VORCID logo; Tan, LendlORCID logo; West, Nicholas PORCID logo; +6 more...Sykes, Melissa L; Hinton, Alexandra O; Bolisetti, Raghu; Avery, Vicky M; Cooper, Matthew AORCID logo; and Blaskovich, Mark ATORCID logo (2022) Nitroimidazopyrazinones with Oral Activity against Tuberculosis and Chagas Disease in Mouse Models of Infection. Journal of Medicinal Chemistry, 65 (19). pp. 13125-13142. ISSN 0022-2623 DOI: 10.1021/acs.jmedchem.2c00972
Copy

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.


picture_as_pdf
Ang_etal_2022_Nitroimidazopyrazinones-with-Oral-Activity-against.pdf
subject
Accepted Version
error
This is an author accepted manuscript version of an article accepted for publication and following peer review. Please be aware that minor differences may exist between this version and the final version if you wish to cite from it.
Available under Creative Commons: Attribution-NonCommercial-No Derivative Works 3.0

View Download

Supplemental Material


Atom BibTeX OpenURL ContextObject in Span Multiline CSV OpenURL ContextObject Dublin Core Dublin Core MPEG-21 DIDL Data Cite XML EndNote HTML Citation JSON MARC (ASCII) MARC (ISO 2709) METS MODS RDF+N3 RDF+N-Triples RDF+XML RIOXX2 XML Reference Manager Refer Simple Metadata ASCII Citation EP3 XML
Export

Downloads