Arylmethylamino steroids as antiparasitic agents

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 Beckmann, Thomas Quack, Christoph G. Grevelding, Anthony B. Pinkerton, Bruno Schönecker, Jeremy Burrows, Elisabeth Davioud-Charvet, Stefan Rahlfs and Katja Becker ()
Additional contact information
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
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)
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
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

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14478

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