dc.contributor.author | Weidner, Thomas | |
dc.contributor.author | Lucantoni, Leonardo | |
dc.contributor.author | Nasereddin, Abed | |
dc.contributor.author | Preu, Lutz | |
dc.contributor.author | Jones, Peter G | |
dc.contributor.author | Dzikowski, Ron | |
dc.contributor.author | Avery, Vicky M | |
dc.contributor.author | Kunick, Conrad | |
dc.date.accessioned | 2017-07-17T12:30:33Z | |
dc.date.available | 2017-07-17T12:30:33Z | |
dc.date.issued | 2017 | |
dc.identifier.issn | 1475-2875 | |
dc.identifier.doi | 10.1186/s12936-017-1839-3 | |
dc.identifier.uri | http://hdl.handle.net/10072/341823 | |
dc.description.abstract | Background: 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.peerreviewed | Yes | |
dc.language | English | |
dc.language.iso | eng | |
dc.publisher | BioMed Central | |
dc.relation.ispartofpagefrom | 192-1 | |
dc.relation.ispartofpageto | 192-10 | |
dc.relation.ispartofjournal | Malaria Journal | |
dc.relation.ispartofvolume | 16 | |
dc.subject.fieldofresearch | Microbiology | |
dc.subject.fieldofresearch | Medical microbiology | |
dc.subject.fieldofresearch | Medical microbiology not elsewhere classified | |
dc.subject.fieldofresearch | Health services and systems | |
dc.subject.fieldofresearch | Public health | |
dc.subject.fieldofresearchcode | 3107 | |
dc.subject.fieldofresearchcode | 3207 | |
dc.subject.fieldofresearchcode | 320799 | |
dc.subject.fieldofresearchcode | 4203 | |
dc.subject.fieldofresearchcode | 4206 | |
dc.title | Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dc.type.code | C - Journal Articles | |
dcterms.license | http://creativecommons.org/licenses/by/4.0/ | |
dc.description.version | Version 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.hasfulltext | Full Text | |
gro.griffith.author | Avery, Vicky M. | |