Show simple item record

dc.contributor.authorWeidner, Thomas
dc.contributor.authorLucantoni, Leonardo
dc.contributor.authorNasereddin, Abed
dc.contributor.authorPreu, Lutz
dc.contributor.authorJones, Peter G
dc.contributor.authorDzikowski, Ron
dc.contributor.authorAvery, Vicky M
dc.contributor.authorKunick, Conrad
dc.date.accessioned2017-07-17T12:30:33Z
dc.date.available2017-07-17T12:30:33Z
dc.date.issued2017
dc.identifier.issn1475-2875
dc.identifier.doi10.1186/s12936-017-1839-3
dc.identifier.urihttp://hdl.handle.net/10072/341823
dc.description.abstractBackground: Malaria is a widespread infectious disease that threatens a large proportion of the population in tropical and subtropical areas. Given the emerging resistance against the current standard anti-malaria chemotherapeutics, the development of alternative drugs is urgently needed. New anti-malarials representing chemotypes unrelated to currently used drugs have an increased potential for displaying novel mechanisms of action and thus exhibit low risk of cross-resistance against established drugs. Results: Phenotypic screening of a small library (32 kinase-inhibitor analogs) against Plasmodium falciparum NF54-luc asexual erythrocytic stage parasites identified a diarylthioether structurally unrelated to registered drugs. Hit expansion led to a series in which the most potent congener displayed nanomolar antiparasitic activity (IC50 = 39 nM, 3D7 strain). Structure–activity relationship analysis revealed a thieno[2,3-d]pyrimidine on one side of the thioether linkage as a prerequisite for antiplasmodial activity. Within the series, the oxazole derivative KuWei173 showed high potency (IC50 = 75 nM; 3D7 strain), good solubility in aqueous solvents (1.33 mM), and >100-fold selectivity toward human cell lines. Rescue experiments identified inhibition of the plasmodial coenzyme A synthesis as a possible mode of action for this compound class. Conclusions: The class of antiplasmodial bishetarylthioethers reported here has been shown to interfere with plasmodial coenzyme A synthesis, a mechanism of action not yet exploited for registered anti-malarial drugs. The oxazole congener KuWei173 displays double-digit nanomolar antiplasmodial activity, selectivity against human cell lines, high drug likeness, and thus represents a promising chemical starting point for further drug development.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherBioMed Central
dc.relation.ispartofpagefrom192-1
dc.relation.ispartofpageto192-10
dc.relation.ispartofjournalMalaria Journal
dc.relation.ispartofvolume16
dc.subject.fieldofresearchMicrobiology
dc.subject.fieldofresearchMedical microbiology
dc.subject.fieldofresearchMedical microbiology not elsewhere classified
dc.subject.fieldofresearchHealth services and systems
dc.subject.fieldofresearchPublic health
dc.subject.fieldofresearchcode3107
dc.subject.fieldofresearchcode3207
dc.subject.fieldofresearchcode320799
dc.subject.fieldofresearchcode4203
dc.subject.fieldofresearchcode4206
dc.titleAntiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
gro.hasfulltextFull Text
gro.griffith.authorAvery, Vicky M.


Files in this item

This item appears in the following Collection(s)

  • Journal articles
    Contains articles published by Griffith authors in scholarly journals.

Show simple item record