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Arylmethylamino steroids as antiparasitic agents

Author

Listed:
  • Reimar Krieg

    (Institute of Anatomy II, University Hospital Jena, Teichgraben 7)

  • Esther Jortzik

    (Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen)

  • Alice-Anne Goetz

    (Université de Strasbourg, CNRS, Inserm, MIR UPR9022/U963)

  • Stéphanie Blandin

    (Université de Strasbourg, CNRS, Inserm, MIR UPR9022/U963)

  • Sergio Wittlin

    (Swiss Tropical and Public Health Institute
    University of Basel)

  • Mourad Elhabiri

    (UMR 7509 Centre National de la Recherche Scientifique and University of Strasbourg, European School of Chemistry, Polymers and Materials (ECPM))

  • Mahsa Rahbari

    (Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen)

  • Selbi Nuryyeva

    (UMR 7509 Centre National de la Recherche Scientifique and University of Strasbourg, European School of Chemistry, Polymers and Materials (ECPM)
    New York University Abu Dhabi)

  • Kerstin Voigt

    (Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI))

  • Hans-Martin Dahse

    (Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI))

  • Axel Brakhage

    (Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI))

  • Svenja Beckmann

    (Institute of Parasitology, Biomedical Research Centre, Justus Liebig University Giessen)

  • Thomas Quack

    (Institute of Parasitology, Biomedical Research Centre, Justus Liebig University Giessen)

  • Christoph G. Grevelding

    (Institute of Parasitology, Biomedical Research Centre, Justus Liebig University Giessen)

  • Anthony B. Pinkerton

    (Conrad Prebys Center for Chemical Genomics, Sanford-Burnham-Prebys Medical Discovery Institute
    Conrad Prebys Center for Chemical Genomics, Sanford-Burnham-Prebys Medical Discovery Institute)

  • Bruno Schönecker

    (Institute of Organic and Macromolecular Chemistry, Friedrich Schiller University Jena)

  • Jeremy Burrows

    (Medicines for Malaria Venture, 20 Route de Pré-Bois)

  • Elisabeth Davioud-Charvet

    (UMR 7509 Centre National de la Recherche Scientifique and University of Strasbourg, European School of Chemistry, Polymers and Materials (ECPM))

  • Stefan Rahlfs

    (Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen)

  • Katja Becker

    (Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen)

Abstract

In search of antiparasitic agents, we here identify arylmethylamino steroids as potent compounds and characterize more than 60 derivatives. The lead compound 1o is fast acting and highly active against intraerythrocytic stages of chloroquine-sensitive and resistant Plasmodium falciparum parasites (IC50 1–5 nM) as well as against gametocytes. In P. berghei-infected mice, oral administration of 1o drastically reduces parasitaemia and cures the animals. Furthermore, 1o efficiently blocks parasite transmission from mice to mosquitoes. The steroid compounds show low cytotoxicity in mammalian cells and do not induce acute toxicity symptoms in mice. Moreover, 1o has a remarkable activity against the blood-feeding trematode parasite Schistosoma mansoni. The steroid and the hydroxyarylmethylamino moieties are essential for antimalarial activity supporting a chelate-based quinone methide mechanism involving metal or haem bioactivation. This study identifies chemical scaffolds that are rapidly internalized into blood-feeding parasites.

Suggested Citation

  • Reimar Krieg & Esther Jortzik & Alice-Anne Goetz & Stéphanie Blandin & Sergio Wittlin & Mourad Elhabiri & Mahsa Rahbari & Selbi Nuryyeva & Kerstin Voigt & Hans-Martin Dahse & Axel Brakhage & Svenja Be, 2017. "Arylmethylamino steroids as antiparasitic agents," Nature Communications, Nature, vol. 8(1), pages 1-12, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14478
    DOI: 10.1038/ncomms14478
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