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Arylmethylamino steroids as antiparasitic agents.

  • Krieg R Institute of Anatomy II, University Hospital Jena, Teichgraben 7, 07743 Jena, Germany.
  • Jortzik E Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen, Heinrich Buff Ring 26-32, 35392 Giessen, Germany.
  • Goetz AA Université de Strasbourg, CNRS, Inserm, MIR UPR9022/U963, F-67000 Strasbourg, France.
  • Blandin S Université de Strasbourg, CNRS, Inserm, MIR UPR9022/U963, F-67000 Strasbourg, France.
  • Wittlin S Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, 4002 Basel, Switzerland.
  • Elhabiri M UMR 7509 Centre National de la Recherche Scientifique and University of Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, France.
  • Rahbari M Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen, Heinrich Buff Ring 26-32, 35392 Giessen, Germany.
  • Nuryyeva S UMR 7509 Centre National de la Recherche Scientifique and University of Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, France.
  • Voigt K Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Adolf-Reichwein-Strasse 23, 07745 Jena, Germany.
  • Dahse HM Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Adolf-Reichwein-Strasse 23, 07745 Jena, Germany.
  • Brakhage A Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Adolf-Reichwein-Strasse 23, 07745 Jena, Germany.
  • Beckmann S Institute of Parasitology, Biomedical Research Centre, Justus Liebig University Giessen, Schubertstrasse 81, 35392 Giessen, Germany.
  • Quack T Institute of Parasitology, Biomedical Research Centre, Justus Liebig University Giessen, Schubertstrasse 81, 35392 Giessen, Germany.
  • Grevelding CG Institute of Parasitology, Biomedical Research Centre, Justus Liebig University Giessen, Schubertstrasse 81, 35392 Giessen, Germany.
  • Pinkerton AB Conrad Prebys Center for Chemical Genomics, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
  • Schönecker B Institute of Organic and Macromolecular Chemistry, Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany.
  • Burrows J Medicines for Malaria Venture, 20 Route de Pré-Bois, 1215 Geneva 15, Switzerland.
  • Davioud-Charvet E UMR 7509 Centre National de la Recherche Scientifique and University of Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, France.
  • Rahlfs S Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen, Heinrich Buff Ring 26-32, 35392 Giessen, Germany.
  • Becker K Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen, Heinrich Buff Ring 26-32, 35392 Giessen, Germany.
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  • 2017-02-18
Published in:
  • Nature communications. - 2017
Amines
Animals
Anopheles
Anti-Infective Agents
Antiparasitic Agents
Cell Death
Cell Proliferation
Female
Germ Cells
Inhibitory Concentration 50
Life Cycle Stages
Malaria
Mice
Models, Biological
Parasites
Plasmodium berghei
Plasmodium falciparum
Schistosoma mansoni
Steroids
Toxicity Tests, Acute
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/176603
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