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  • Design and Synthesis of Novel Anti-Plasmodial Histone Deacetylase Inhibitors Containing an Alkoxyamide Connecting Unit

    Author(s)
    Avelar, Leandro A Alves
    Held, Jana
    Engel, Jessica A
    Sureechatchaiyan, Parichat
    Hansen, Finn K
    Hamacher, Alexandra
    Kassack, Matthias U
    Mordmueller, Benjamin
    Andrews, Katherine T
    Kurz, Thomas
    Griffith University Author(s)
    Andrews, Katherine T.
    Engel, Jess
    Year published
    2017
    Metadata
    Show full item record
    Abstract
    Despite recent declines in mortality, malaria remains an important global health problem. New therapies are needed, including new drugs with novel modes of action compared to existing agents. Among new potential therapeutic targets for malaria, inhibition of parasitic histone deacetylases (HDACs) is a promising approach. Homology modeling of PfHDAC1, a known target of some anti-plasmodial HDAC inhibitors, revealed a unique threonine residue at the rim of the active site in close proximity to the location of the cap group of vorinostat-type HDAC inhibitors. Aiming to obtain HDAC inhibitors with potent and preferential ...
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    Despite recent declines in mortality, malaria remains an important global health problem. New therapies are needed, including new drugs with novel modes of action compared to existing agents. Among new potential therapeutic targets for malaria, inhibition of parasitic histone deacetylases (HDACs) is a promising approach. Homology modeling of PfHDAC1, a known target of some anti-plasmodial HDAC inhibitors, revealed a unique threonine residue at the rim of the active site in close proximity to the location of the cap group of vorinostat-type HDAC inhibitors. Aiming to obtain HDAC inhibitors with potent and preferential anti-plasmodial activity, we synthesized a mini-library of alkoxyamide-based HDAC inhibitors containing hydrogen bond acceptors in the cap group. Using a 5-step synthetic route, 12 new inhibitors were synthesized and assayed against Plasmodium falciparum asexual blood stage parasites (clones 3D7 and Dd2) and human cells (HepG2). The most active compound 6h (Pf3D7 IC50: 0.07 µM; PfDd2 IC50: 0.07 µM) was 25-fold more toxic against the parasite versus human HepG2 cells. Selected compounds were shown to cause hyperacetylation of P. falciparum histone H4, indicating inhibition of one or more PfHDACs.
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    Journal Title
    Archiv der Pharmazie
    Volume
    350
    DOI
    https://doi.org/10.1002/ardp.201600347
    Subject
    Medicinal and Biomolecular Chemistry not elsewhere classified
    Medicinal and Biomolecular Chemistry
    Pharmacology and Pharmaceutical Sciences
    Publication URI
    http://hdl.handle.net/10072/345027
    Collection
    • Journal articles

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