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dc.contributor.authorKlejch, T
dc.contributor.authorKeough, DT
dc.contributor.authorChavchich, M
dc.contributor.authorTravis, J
dc.contributor.authorSkácel, J
dc.contributor.authorPohl, R
dc.contributor.authorJaneba, Z
dc.contributor.authorEdstein, MD
dc.contributor.authorAvery, VM
dc.contributor.authorGuddat, LW
dc.contributor.authorHocková, D
dc.date.accessioned2019-09-30T00:52:54Z
dc.date.available2019-09-30T00:52:54Z
dc.date.issued2019
dc.identifier.issn0223-5234
dc.identifier.doi10.1016/j.ejmech.2019.111667
dc.identifier.urihttp://hdl.handle.net/10072/387884
dc.description.abstractHypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is a recognized target for antimalarial chemotherapeutics. It synthesises all of the 6-oxopurine nucleoside monophosphates, IMP, GMP and XMP needed by the malarial parasite, Plasmodium falciparum (Pf). PfHGXPRT is also indirectly responsible for the synthesis of the adenosine monophosphate, AMP. The acyclic nucleoside phosphonates (ANPs) are a class of PfHGXPRT inhibitors. Prodrugs of these compounds are able to arrest the growth of Pf in cell culture. In the search for new inhibitors of PfHGXPRT, a series of sulfur containing ANPs (thia-ANPs) has been designed and synthesized. These compounds are based on the structure of 2-(phosphonoethoxy)ethylguanine (PEEG) and PEEHx which consist of a purine base (i.e. guanine or hypoxanthine) linked to a phosphonate group by five atoms i.e. four carbons and one oxygen. Here, PEEG and PEEHx were modified by substituting a sulfide, sulfoxide or a sulfone bridge for the oxygen atom in the linker. The effect of these substitutions on the Ki values for human HGPRT and PfHGXPRT was investigated and showed that most of the thia-ANPs distinctively favour PfHGXPRT. For example, the thia-analogue of PEEHx has a Ki value of 0.2 μM for PfHGXPRT, a value 25-fold lower than for the human counterpart. Prodrugs of these compounds have IC50 values in the 4–6 μM range in antimalarial cell-based assays, making them attractive compounds for further development as antimalarial drug leads.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherElsevier - Masson
dc.publisher.placeFrance
dc.relation.ispartofpagefrom111667: 1
dc.relation.ispartofpageto111667: 15
dc.relation.ispartofjournalEuropean Journal of Medicinal Chemistry
dc.relation.ispartofvolume183
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry
dc.subject.fieldofresearchOrganic Chemistry
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences
dc.subject.fieldofresearchcode0304
dc.subject.fieldofresearchcode0305
dc.subject.fieldofresearchcode1115
dc.subject.keywordsAcyclic nucleoside phosphonates
dc.subject.keywordsHypoxanthine-guanine-xanthine phosphoribosyltransferase
dc.subject.keywordsPlasmodium falciparum
dc.subject.keywordsSulfide oxidation
dc.subject.keywordsSulfur-containing drugs
dc.titleSulfide, sulfoxide and sulfone bridged acyclic nucleoside phosphonates as inhibitors of the Plasmodium falciparum and human 6-oxopurine phosphoribosyltransferases: Synthesis and evaluation
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationKlejch, T; Keough, DT; Chavchich, M; Travis, J; Skácel, J; Pohl, R; Janeba, Z; Edstein, MD; Avery, VM; Guddat, LW; Hocková, D, Sulfide, sulfoxide and sulfone bridged acyclic nucleoside phosphonates as inhibitors of the Plasmodium falciparum and human 6-oxopurine phosphoribosyltransferases: Synthesis and evaluation, European Journal of Medicinal Chemistry, 2019, 183, pp. 111667: 1-111667: 15
dcterms.dateAccepted2019-08-30
dcterms.licensehttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated2019-09-30T00:22:56Z
dc.description.versionAccepted Manuscript (AM)
gro.rights.copyright© 2019 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence, which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorAvery, Vicky M.


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