Ang, Chee Wei; Lee, Brendon M; Jackson, Colin J; Wang, Yuehong; Franzblau, Scott G; Francisco, Amanda F; Kelly, John M; Bernhardt, Paul V; Tan, Lendl; West, Nicholas P; +6 more... Sykes, Melissa L; Hinton, Alexandra O; Bolisetti, Raghu; Avery, Vicky M; Cooper, Matthew A; Blaskovich, Mark AT; (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: https://doi.org/10.1021/acs.jmedchem.2c00972
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Abstract
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.
Item Type | Article |
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Faculty and Department | Faculty of Infectious and Tropical Diseases > Department of Infection Biology |
PubMed ID | 36111399 |
Elements ID | 183723 |
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Licence: Creative Commons: Attribution-Noncommercial-No Derivative Works 3.0
Embargo Date: 16 September 2023
Restricted to: Repository staff only
Filename: Ang_etal_2022_Nitroimidazopyrazinones-with-Oral-Activity-against-SUP.pdf
Description: 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.
Licence: Creative Commons: Attribution-Noncommercial-No Derivative Works 3.0