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dc.contributor.authorHansen, Finn K
dc.contributor.authorSumanadasa, Subathdrage DM
dc.contributor.authorStenzel, Katharina
dc.contributor.authorDuffy, Sandra
dc.contributor.authorMeister, Stephan
dc.contributor.authorMarek, Linda
dc.contributor.authorSchmetter, Rebekka
dc.contributor.authorKuna, Krystina
dc.contributor.authorHamacher, Alexandra
dc.contributor.authorMordmueller, Benjamin
dc.contributor.authorKassack, Matthias U
dc.contributor.authorWinzeler, Elizabeth A
dc.contributor.authorAvery, Vicky M
dc.contributor.authorAndrews, Katherine T
dc.contributor.authorKurz, Thomas
dc.date.accessioned2017-05-03T14:33:01Z
dc.date.available2017-05-03T14:33:01Z
dc.date.issued2014
dc.identifier.issn0223-5234
dc.identifier.doi10.1016/j.ejmech.2014.05.050
dc.identifier.urihttp://hdl.handle.net/10072/63967
dc.description.abstractIn this work we investigated the antiplasmodial activity of a series of HDAC inhibitors containing an alkoxyamide connecting-unit linker region. HDAC inhibitor 1a (LMK235), previously shown to be a novel and specific inhibitor of human HDAC4 and 5, was used as a starting point to rapidly construct a mini-library of HDAC inhibitors using a straightforward solid-phase supported synthesis. Several of these novel HDAC inhibitors were found to have potent in vitro activity against asexual stage Plasmodium falciparum malaria parasites. Representative compounds were shown to hyperacetylate P. falciparum histones and to inhibit deacetylase activity of recombinant PfHDAC1 and P. falciparum nuclear extracts. All compounds were also screened in vitro for activity against Plasmodium berghei exo-erythrocytic stages and selected compounds were further tested against late stage (IV and V) P. falciparum gametocytes. Of note, some compounds showed nanomolar activity against all three life cycle stages tested (asexual, exo-erythrocytic and gametocyte stages) and several compounds displayed significantly increased parasite selectivity compared to the reference HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). These data suggest that it may be possible to develop HDAC inhibitors that target multiple malaria parasite life cycle stages.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherElsevier - Masson
dc.publisher.placeFrance
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom204
dc.relation.ispartofpageto213
dc.relation.ispartofjournalEuropean Journal of Medicinal Chemistry
dc.relation.ispartofvolume82
dc.rights.retentionY
dc.subject.fieldofresearchMedicinal and biomolecular chemistry
dc.subject.fieldofresearchMedicinal and biomolecular chemistry not elsewhere classified
dc.subject.fieldofresearchOrganic chemistry
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchcode3404
dc.subject.fieldofresearchcode340499
dc.subject.fieldofresearchcode3405
dc.subject.fieldofresearchcode3214
dc.titleDiscovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorAndrews, Katherine T.
gro.griffith.authorDuffy, Sandra
gro.griffith.authorAvery, Vicky M.


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