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

Show simple item record Thompson AM O'Connor PD Marshall AJ Francisco AF Kelly JM Riley J Read KD Perez CJ Cornwall S Thompson RCA Keenan M White KL Charman SA Zulfiqar B Sykes ML Avery VM Chatelain E Denny WA 2020-11-09T01:19:27Z 2020-11-09T01:19:27Z 2020-12-1
dc.identifier.citation European journal of medicinal chemistry 207:112849 Dec 2020
dc.identifier.issn 1768-3254
dc.description.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.
dc.publisher Elsevier
dc.relation.ispartofseries European Journal of Medicinal Chemistry
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.
dc.subject Chagas disease
dc.subject Pretomanid
dc.subject Library screening
dc.subject In vivo efficacy
dc.subject Pharmacokinetics
dc.subject Bioluminescence imaging
dc.subject 0304 Medicinal And Biomolecular Chemistry
dc.subject 1115 Pharmacology And Pharmaceutical Sciences
dc.subject 0305 Organic Chemistry
dc.title Re-evaluating pretomanid analogues for Chagas disease: hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy
dc.type Journal Article
dc.identifier.doi 10.1016/j.ejmech.2020.112849
pubs.volume 207 2020-10-08T20:12:30Z
dc.rights.holder Copyright: 2020 Elsevier Masson SAS. en
dc.rights.accessrights en
pubs.subtype Article
pubs.elements-id 817681
pubs.number 112849 2020-9-18

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