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  • Design and Synthesis of Terephthalic Acid-Based Histone Deacetylase Inhibitors with Dual-Stage Anti-Plasmodium Activity

    Author(s)
    Stenzel, Katharina
    Chua, Ming Jang
    Duffy, Sandra
    Antonova-Koch, Yevgeniya
    Meister, Stephan
    Hamacher, Alexandra
    Kassack, Matthias U
    Winzeler, Elizabeth
    Avery, Vicky M
    Kurz, Thomas
    Andrews, Katherine T
    Hansen, Finn K
    Griffith University Author(s)
    Andrews, Katherine T.
    Duffy, Sandra
    Avery, Vicky M.
    Chua, MJ J.
    Stenzel, Katharina
    Year published
    2017
    Metadata
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    Abstract
    In this work we aimed to develop parasite-selective histone deacetylase inhibitors (HDAC) inhibitors with activity against the disease-causing asexual blood stages of Plasmodium as well as causal prophylactic and/or transmission blocking properties. We report the design, synthesis, and biological testing of a series of 13 terephthalic acid-based HDAC inhibitors. All compounds showed low cytotoxicity against human embryonic kidney (HEK293) cells (IC50: 8–>51 μm), with 11 also having sub-micromolar in vitro activity against drug-sensitive (3D7) and multidrug-resistant (Dd2) asexual blood-stage P. falciparum parasites ...
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    In this work we aimed to develop parasite-selective histone deacetylase inhibitors (HDAC) inhibitors with activity against the disease-causing asexual blood stages of Plasmodium as well as causal prophylactic and/or transmission blocking properties. We report the design, synthesis, and biological testing of a series of 13 terephthalic acid-based HDAC inhibitors. All compounds showed low cytotoxicity against human embryonic kidney (HEK293) cells (IC50: 8–>51 μm), with 11 also having sub-micromolar in vitro activity against drug-sensitive (3D7) and multidrug-resistant (Dd2) asexual blood-stage P. falciparum parasites (IC50≈0.1–0.5 μm). A subset of compounds were examined for activity against early- and late-stage P. falciparum gametocytes and P. berghei exo-erythrocytic-stage parasites. While only moderate activity was observed against gametocytes (IC50>2 μm), the most active compound (N1-((3,5-dimethylbenzyl)oxy)-N4-hydroxyterephthalamide, 1 f) showed sub-micromolar activity against P. berghei exo-erythrocytic stages (IC50 0.18 μm) and >270-fold better activity for exo-erythrocytic forms than for HepG2 cells. This, together with asexual-stage in vitro potency (IC50≈0.1 μm) and selectivity of this compound versus human cells (SI>450), suggests that 1 f may be a valuable starting point for the development of novel antimalarial drug leads with low host cell toxicity and multi-stage anti-plasmodial activity.
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    Journal Title
    ChemMedChem
    Volume
    12
    DOI
    https://doi.org/10.1002/cmdc.201700360
    Subject
    Medicinal and Biomolecular Chemistry not elsewhere classified
    Medicinal and Biomolecular Chemistry
    Organic Chemistry
    Pharmacology and Pharmaceutical Sciences
    Publication URI
    http://hdl.handle.net/10072/368333
    Collection
    • Journal articles

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