2. Academic Validation
  3. Re-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy

Re-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy

  • Eur J Med Chem. 2020 Dec 1;207:112849. doi: 10.1016/j.ejmech.2020.112849.
Andrew M Thompson 1,  Patrick D O'Connor 2,  Andrew J Marshall 2,  Amanda F Francisco 3,  John M Kelly 3,  Jennifer Riley 4,  Kevin D Read 4,  Catherine J Perez 5,  Scott Cornwall 5,  R C Andrew Thompson 5,  Martine Keenan 6,  Karen L White 7,  Susan A Charman 7,  Bilal Zulfiqar 8,  Melissa L Sykes 8,  Vicky M Avery 8,  Eric Chatelain 9,  William A Denny 2
Affiliations

Affiliations

  • 1 Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand. Electronic address: [email protected].
  • 2 Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
  • 3 Department of Infection Biology, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom.
  • 4 Drug Discovery Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, United Kingdom.
  • 5 Department of Parasitology & Veterinary Sciences, Murdoch University, South Street, Murdoch, Western Australia, 6150, Australia.
  • 6 Epichem Pty Ltd, Suite 5, 3 Brodie-Hall Drive, Technology Park, Bentley, Western Australia, 6102, Australia.
  • 7 Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
  • 8 Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, Queensland, 4111, Australia.
  • 9 Drugs for Neglected Diseases initiative, 15 Chemin Louis Dunant, 1202, Geneva, Switzerland.
PMID: 33007723 DOI: 10.1016/j.ejmech.2020.112849
Abstract

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the Parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic Infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class.

Keywords

Bioluminescence imaging; Chagas disease; In vivo efficacy; Library screening; Pharmacokinetics; Pretomanid.

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