2. Academic Validation
  3. Nitroimidazopyrazinones with Oral Activity against Tuberculosis and Chagas Disease in Mouse Models of Infection

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

  • J Med Chem. 2022 Oct 13;65(19):13125-13142. doi: 10.1021/acs.jmedchem.2c00972.
Chee Wei Ang 1 2,  Brendon M Lee 3 4,  Colin J Jackson 3,  Yuehong Wang 5,  Scott G Franzblau 5,  Amanda F Francisco 6,  John M Kelly 6,  Paul V Bernhardt 7,  Lendl Tan 7,  Nicholas P West 7,  Melissa L Sykes 8,  Alexandra O Hinton 1,  Raghu Bolisetti 1,  Vicky M Avery 8 9,  Matthew A Cooper 1,  Mark A T Blaskovich 1
Affiliations

Affiliations

  • 1 Center for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
  • 2 School of Science, Monash University Malaysia, Subang Jaya, 47500 Selangor, Malaysia.
  • 3 Research School of Chemistry, Australian National University, Sullivans Creek Road, Acton ACT 2601, Australia.
  • 4 Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College, New York, New York 10021, United States.
  • 5 Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
  • 6 Department of Infection Biology, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom.
  • 7 School of Chemistry and Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
  • 8 Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, Queensland 4111, Australia.
  • 9 School of Environment and Science, Griffith University, Nathan, Queensland 4111, Australia.
PMID: 36111399 DOI: 10.1021/acs.jmedchem.2c00972
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.

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