Show simple item record

dc.contributor.authorDow, Geoffrey S
dc.contributor.authorChen, Yufeng
dc.contributor.authorAndrews, Katherine T
dc.contributor.authorCaridha, Diana
dc.contributor.authorGerena, Lucia
dc.contributor.authorGettayacamin, Montip
dc.contributor.authorJohnson, Jacob
dc.contributor.authorLi, Qigui
dc.contributor.authorMelendez, Victor
dc.contributor.authorObaldia, Nicanor
dc.contributor.authorTran, Thanh N
dc.contributor.authorKozikowski, Alan P
dc.date.accessioned2017-09-05T01:31:11Z
dc.date.available2017-09-05T01:31:11Z
dc.date.issued2008
dc.date.modified2014-10-08T01:43:45Z
dc.identifier.issn0066-4804
dc.identifier.doi10.1128/AAC.00439-08
dc.identifier.urihttp://hdl.handle.net/10072/23290
dc.description.abstractThe antimalarial activity and pharmacology of a series of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors (HDACIs) was evaluated. In in vitro growth inhibition assays approximately 50 analogs were evaluated against four drug resistant strains of Plasmodium falciparum. The range of 50% inhibitory concentrations (IC50s) was 0.0005 to >1 μM. Five analogs exhibited IC50s of <3 nM, and three of these exhibited selectivity indices of >600. The most potent compound, WR301801 (YC-2-88) was shown to cause hyperacetylation of P. falciparum histones, which is a marker for HDAC inhibition in eukaryotic cells. The compound also inhibited malarial and mammalian HDAC activity in functional assays at low nanomolar concentrations. WR301801 did not exhibit cures in P. berghei-infected mice at oral doses as high as 640 mg/kg/day for 3 days or in P. falciparum-infected Aotus lemurinus lemurinus monkeys at oral doses of 32 mg/kg/day for 3 days, despite high relative bioavailability. The failure of monotherapy in mice may be due to a short half-life, since the compound was rapidly hydrolyzed to an inactive acid metabolite by loss of its hydroxamate group in vitro (half-life of 11 min in mouse microsomes) and in vivo (half-life in mice of 3.5 h after a single oral dose of 50 mg/kg). However, WR301801 exhibited cures in P. berghei-infected mice when combined at doses of 52 mg/kg/day orally with subcurative doses of chloroquine. Next-generation HDACIs with greater metabolic stability than WR301801 may be useful as antimalarials if combined appropriately with conventional antimalarial drugs.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Society for Microbiology
dc.publisher.placeUSA
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom3467
dc.relation.ispartofpageto3477
dc.relation.ispartofissue10
dc.relation.ispartofjournalAntimicrobial Agents and Chemotherapy
dc.relation.ispartofvolume52
dc.rights.retentionY
dc.subject.fieldofresearchMicrobiology
dc.subject.fieldofresearchMedical microbiology
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchBasic pharmacology
dc.subject.fieldofresearchcode3107
dc.subject.fieldofresearchcode3207
dc.subject.fieldofresearchcode3214
dc.subject.fieldofresearchcode321401
dc.titleAntimalarial activity of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2008 American Society for Microbiology. The attached file is reproduced here in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
gro.date.issued2008
gro.hasfulltextFull Text
gro.griffith.authorAndrews, Katherine T.


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