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  • Antimalarial activity of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors

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    Author(s)
    Dow, Geoffrey S
    Chen, Yufeng
    Andrews, Katherine T
    Caridha, Diana
    Gerena, Lucia
    Gettayacamin, Montip
    Johnson, Jacob
    Li, Qigui
    Melendez, Victor
    Obaldia, Nicanor
    Tran, Thanh N
    Kozikowski, Alan P
    Griffith University Author(s)
    Andrews, Katherine T.
    Tran, Thanh
    Year published
    2008
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    Abstract
    The 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. ...
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    The 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.
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    Journal Title
    Antimicrobial Agents and Chemotherapy
    Volume
    52
    Issue
    10
    DOI
    https://doi.org/10.1128/AAC.00439-08
    Copyright Statement
    © 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.
    Subject
    Basic Pharmacology
    Microbiology
    Medical Microbiology
    Pharmacology and Pharmaceutical Sciences
    Publication URI
    http://hdl.handle.net/10072/23290
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    • Journal articles

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