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Re-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy.
Thompson, Andrew M; O'Connor, Patrick D; Marshall, Andrew J; Francisco, Amanda F; Kelly, John M; Riley, Jennifer; Read, Kevin D; Perez, Catherine J; Cornwall, Scott; Thompson, R C Andrew; Keenan, Martine; White, Karen L; Charman, Susan A; Zulfiqar, Bilal; Sykes, Melissa L; Avery, Vicky M; Chatelain, Eric; Denny, William A.
Afiliação
  • Thompson AM; Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand. Electronic address: am.thompson@auckland.ac.nz.
  • O'Connor PD; Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
  • Marshall AJ; Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
  • Francisco AF; Department of Infection Biology, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom.
  • Kelly JM; Department of Infection Biology, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom.
  • Riley J; Drug Discovery Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, United Kingdom.
  • Read KD; Drug Discovery Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, United Kingdom.
  • Perez CJ; Department of Parasitology & Veterinary Sciences, Murdoch University, South Street, Murdoch, Western Australia, 6150, Australia.
  • Cornwall S; Department of Parasitology & Veterinary Sciences, Murdoch University, South Street, Murdoch, Western Australia, 6150, Australia.
  • Thompson RCA; Department of Parasitology & Veterinary Sciences, Murdoch University, South Street, Murdoch, Western Australia, 6150, Australia.
  • Keenan M; Epichem Pty Ltd, Suite 5, 3 Brodie-Hall Drive, Technology Park, Bentley, Western Australia, 6102, Australia.
  • White KL; Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
  • Charman SA; Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
  • Zulfiqar B; Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, Queensland, 4111, Australia.
  • Sykes ML; Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, Queensland, 4111, Australia.
  • Avery VM; Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, Queensland, 4111, Australia.
  • Chatelain E; Drugs for Neglected Diseases initiative, 15 Chemin Louis Dunant, 1202, Geneva, Switzerland.
  • Denny WA; Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
Eur J Med Chem ; 207: 112849, 2020 Dec 01.
Article em En | MEDLINE | ID: mdl-33007723
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tripanossomicidas / Trypanosoma cruzi / Doença de Chagas / Nitroimidazóis Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tripanossomicidas / Trypanosoma cruzi / Doença de Chagas / Nitroimidazóis Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article