Journal article
Re-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy
European Journal of Medicinal Chemistry, Vol.207, Art. 112849
2020
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.
Details
- Title
- Re-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy
- Authors/Creators
- A.M. Thompson (Author/Creator) - University of AucklandP.D. O’Connor (Author/Creator)A.J. Marshall (Author/Creator) - University of AucklandA.F. Francisco (Author/Creator) - University of LondonJ.M. Kelly (Author/Creator) - University of LondonJ. Riley (Author/Creator) - University of DundeeK.D. Read (Author/Creator) - University of DundeeC.J. Perez (Author/Creator) - Murdoch UniversityS. Cornwall (Author/Creator) - Murdoch UniversityR.C.A. Thompson (Author/Creator) - Murdoch UniversityM. Keenan (Author/Creator) - Bentley (Germany)K.L. White (Author/Creator) - Monash UniversityS.A. Charman (Author/Creator) - Monash UniversityB. Zulfiqar (Author/Creator) - Griffith UniversityM.L. Sykes (Author/Creator) - Griffith UniversityV.M. Avery (Author/Creator) - Griffith UniversityE. Chatelain (Author/Creator) - Drugs for Neglected Diseases InitiativeW.A. Denny (Author/Creator) - University of Auckland
- Publication Details
- European Journal of Medicinal Chemistry, Vol.207, Art. 112849
- Publisher
- Elsevier Masson SAS
- Identifiers
- 991005542463107891
- Copyright
- © 2020 Elsevier Masson SAS.
- Murdoch Affiliation
- School of Veterinary Medicine
- Language
- English
- Resource Type
- Journal article
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Source: InCites
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.261 Parasitology - Trypanosoma & Leishmania
- 1.261.596 Trypanosoma Biology
- Web Of Science research areas
- Chemistry, Medicinal
- ESI research areas
- Chemistry