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dc.contributor.authorThompson, Andrew M
dc.contributor.authorO'Connor, Patrick D
dc.contributor.authorMarshall, Andrew J
dc.contributor.authorFrancisco, Amanda F
dc.contributor.authorKelly, John M
dc.contributor.authorRiley, Jennifer
dc.contributor.authorRead, Kevin D
dc.contributor.authorPerez, Catherine J
dc.contributor.authorCornwall, Scott
dc.contributor.authorThompson, RC Andrew
dc.contributor.authorKeenan, Martine
dc.contributor.authorWhite, Karen L
dc.contributor.authorCharman, Susan A
dc.contributor.authorZulfiqar, Bilal
dc.contributor.authorSykes, Melissa L
dc.contributor.authorAvery, Vicky M
dc.contributor.authorChatelain, Eric
dc.contributor.authorDenny, William A
dc.date.accessioned2020-10-12T03:32:56Z
dc.date.available2020-10-12T03:32:56Z
dc.date.issued2020
dc.identifier.issn0223-5234
dc.identifier.doi10.1016/j.ejmech.2020.112849
dc.identifier.urihttp://hdl.handle.net/10072/398275
dc.description.abstractPhenotypic 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.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherElsevier
dc.relation.ispartofjournalEur J Med Chem
dc.relation.ispartofvolume207
dc.subject.fieldofresearchMedicinal and biomolecular chemistry
dc.subject.fieldofresearchOrganic chemistry
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchcode3404
dc.subject.fieldofresearchcode3405
dc.subject.fieldofresearchcode3214
dc.subject.keywordsBioluminescence imaging
dc.subject.keywordsChagas disease
dc.subject.keywordsIn vivo efficacy
dc.subject.keywordsLibrary screening
dc.subject.keywordsPharmacokinetics
dc.titleRe-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationThompson, 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, 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, 207
dcterms.dateAccepted2020-09-12
dc.date.updated2020-10-12T01:33:25Z
gro.hasfulltextNo Full Text
gro.griffith.authorAvery, Vicky M.
gro.griffith.authorZulfiqar, Bilal
gro.griffith.authorSykes, Melissa L.


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