• myGriffith
    • Staff portal
    • Contact Us⌄
      • Future student enquiries 1800 677 728
      • Current student enquiries 1800 154 055
      • International enquiries +61 7 3735 6425
      • General enquiries 07 3735 7111
      • Online enquiries
      • Staff phonebook
    View Item 
    •   Home
    • Griffith Research Online
    • Journal articles
    • View Item
    • Home
    • Griffith Research Online
    • Journal articles
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

  • All of Griffith Research Online
    • Communities & Collections
    • Authors
    • By Issue Date
    • Titles
  • This Collection
    • Authors
    • By Issue Date
    • Titles
  • Statistics

  • Most Popular Items
  • Statistics by Country
  • Most Popular Authors
  • Support

  • Contact us
  • FAQs
  • Admin login

  • Login
  • Investigation of the in vitro and in vivo efficacy of peptoid-based HDAC inhibitors with dual-stage antiplasmodial activity

    Author(s)
    Mackwitz, Marcel KW
    Hesping, Eva
    Eribez, Korina
    Schöler, Andrea
    Antonova-Koch, Yevgeniya
    Held, Jana
    Winzeler, Elizabeth A
    Andrews, Katherine T
    Hansen, Finn K
    Griffith University Author(s)
    Andrews, Katherine T.
    Hesping, Eva M.
    Year published
    2020
    Metadata
    Show full item record
    Abstract
    Histone deacetylases (HDACs) have been identified as emerging antiplasmodial drug targets. In this work, we report on the synthesis, structure-activity relationships, metabolic stability and in vivo efficacy of new peptoid-based HDAC inhibitors with dual-stage antiplasmodial activity. A mini library of HDAC inhibitors was synthesized using a one-pot, multi-component protocol or submonomer pathways. The screening of the target compounds for their activity against asexual blood stage parasites, human cell cytotoxicity, liver stage parasites, and selected human HDAC isoforms provided important structure-activity relationship ...
    View more >
    Histone deacetylases (HDACs) have been identified as emerging antiplasmodial drug targets. In this work, we report on the synthesis, structure-activity relationships, metabolic stability and in vivo efficacy of new peptoid-based HDAC inhibitors with dual-stage antiplasmodial activity. A mini library of HDAC inhibitors was synthesized using a one-pot, multi-component protocol or submonomer pathways. The screening of the target compounds for their activity against asexual blood stage parasites, human cell cytotoxicity, liver stage parasites, and selected human HDAC isoforms provided important structure-activity relationship data. The most promising HDAC inhibitor from this series, compound 3n, demonstrated potent activity against drug-sensitive and drug-resistant asexual stage P. falciparum parasites and was selective for the parasite versus human cells (Pf3D7 IC50 0.016 μM; SIHepG2/Pf3D7 573; PfDd2 IC50 0.002 μM; SIHepG2/PfDd2 4580) combined with activity against P. berghei exoerythrocytic liver stages (PbEEF IC50 0.48 μM). While compound 3n displayed high stability in human (Clint 5 μL/min/mg) and mouse (Clint 6 μL/min/mg) liver microsomes, only modest oral in vivo efficacy was observed in P. berghei infected mice. Together these data provide a foundation for future work to improve the properties of these dual-stage inhibitors as drug leads for malaria.
    View less >
    Journal Title
    European Journal of Medicinal Chemistry
    Volume
    211
    DOI
    https://doi.org/10.1016/j.ejmech.2020.113065
    Subject
    Medicinal and Biomolecular Chemistry
    Organic Chemistry
    Pharmacology and Pharmaceutical Sciences
    Asexual
    Exoerythrocytic
    HDAC inhibitors
    Histone deacetylase
    Malaria
    Publication URI
    http://hdl.handle.net/10072/400689
    Collection
    • Journal articles

    Footer

    Disclaimer

    • Privacy policy
    • Copyright matters
    • CRICOS Provider - 00233E

    Tagline

    • Gold Coast
    • Logan
    • Brisbane - Queensland, Australia
    First Peoples of Australia
    • Aboriginal
    • Torres Strait Islander