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  • One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites

    Author(s)
    Diedrich, Daniela
    Stenzel, Katharina
    Hesping, Eva
    Antonova-Koch, Yevgeniya
    Gebru, Tamirat
    Duffy, Sandra
    Fisher, Gillian
    Schoeler, Andrea
    Meister, Stephan
    Kurz, Thomas
    Avery, Vicky M
    Winzeler, Elizabeth A
    Held, Jana
    Andrews, Katherine T
    Hansen, Finn K
    Griffith University Author(s)
    Andrews, Katherine T.
    Duffy, Sandra
    Avery, Vicky M.
    Fisher, Gill M.
    Year published
    2018
    Metadata
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    Abstract
    Malaria drug discovery has shifted from a focus on targeting asexual blood stage parasites, to the development of drugs that can also target exo-erythrocytic forms and/or gametocytes in order to prevent malaria and/or parasite transmission. In this work, we aimed to develop parasite-selective histone deacetylase inhibitors (HDACi) with activity against the disease-causing asexual blood stages of Plasmodium malaria parasites as well as with causal prophylactic and/or transmission blocking properties. An optimized one-pot, multi-component protocol via a sequential Ugi four-component reaction and hydroxylaminolysis was used for ...
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    Malaria drug discovery has shifted from a focus on targeting asexual blood stage parasites, to the development of drugs that can also target exo-erythrocytic forms and/or gametocytes in order to prevent malaria and/or parasite transmission. In this work, we aimed to develop parasite-selective histone deacetylase inhibitors (HDACi) with activity against the disease-causing asexual blood stages of Plasmodium malaria parasites as well as with causal prophylactic and/or transmission blocking properties. An optimized one-pot, multi-component protocol via a sequential Ugi four-component reaction and hydroxylaminolysis was used for the preparation of a panel of peptoid-based HDACi. Several compounds displayed potent activity against drug-sensitive and drug-resistant P. falciparum asexual blood stages, high parasite-selectivity and submicromolar activity against exo-erythrocytic forms of P. berghei. Our optimization study resulted in the discovery of the hit compound 1u which combines high activity against asexual blood stage parasites (Pf 3D7 IC50: 4 nM; Pf Dd2 IC50: 1 nM) and P. berghei exo-erythrocytic forms (Pb EEF IC50: 25 nM) with promising parasite-specific activity (SIPf3D7/HepG2: 2496, SIPfDd2/HepG2: 9990, and SIPbEEF/HepG2: 400).
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    Journal Title
    European Journal of Medicinal Chemistry
    Volume
    158
    DOI
    https://doi.org/10.1016/j.ejmech.2018.09.018
    Subject
    Medicinal and biomolecular chemistry
    Medicinal and biomolecular chemistry not elsewhere classified
    Organic chemistry
    Pharmacology and pharmaceutical sciences
    Publication URI
    http://hdl.handle.net/10072/382121
    Collection
    • Journal articles

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