title: Arylmethylamino steroids as antiparasitic agents.
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 (IC501-5 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.
authors.affiliation: Institute of Anatomy II, University Hospital Jena, Teichgraben 7, 07743 Jena, Germany.
authors.forename: Reimar
authors.initials: R
authors.lastname: Krieg
authors.affiliation: Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen, Heinrich Buff Ring 26-32, 35392 Giessen, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Jortzik
authors.affiliation: Université de Strasbourg, CNRS, Inserm, MIR UPR9022/U963, F-67000 Strasbourg, France.
authors.forename: Alice-Anne
authors.initials: AA
authors.lastname: Goetz
authors.affiliation: Université de Strasbourg, CNRS, Inserm, MIR UPR9022/U963, F-67000 Strasbourg, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Blandin
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, 4002 Basel, Switzerland.|University of Basel, Petersplatz 1, 4001 Basel, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.affiliation: 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.
authors.forename: Mourad
authors.initials: M
authors.lastname: Elhabiri
authors.affiliation: Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen, Heinrich Buff Ring 26-32, 35392 Giessen, Germany.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Rahbari
authors.affiliation: 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.|New York University Abu Dhabi, PO Box 129188, Abu Dhabi, UAE.
authors.forename: Selbi
authors.initials: S
authors.lastname: Nuryyeva
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Adolf-Reichwein-Strasse 23, 07745 Jena, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Voigt
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Adolf-Reichwein-Strasse 23, 07745 Jena, Germany.
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Dahse
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Adolf-Reichwein-Strasse 23, 07745 Jena, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Brakhage
authors.affiliation: Institute of Parasitology, Biomedical Research Centre, Justus Liebig University Giessen, Schubertstrasse 81, 35392 Giessen, Germany.
authors.forename: Svenja
authors.initials: S
authors.lastname: Beckmann
authors.affiliation: Institute of Parasitology, Biomedical Research Centre, Justus Liebig University Giessen, Schubertstrasse 81, 35392 Giessen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quack
authors.affiliation: Institute of Parasitology, Biomedical Research Centre, Justus Liebig University Giessen, Schubertstrasse 81, 35392 Giessen, Germany.
authors.forename: Christoph G
authors.initials: CG
authors.lastname: Grevelding
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.|Conrad Prebys Center for Chemical Genomics, Sanford-Burnham-Prebys Medical Discovery Institute, 6400 Sanger Road, Orlando, Florida 32827, USA.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Pinkerton
authors.affiliation: Institute of Organic and Macromolecular Chemistry, Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Schönecker
authors.affiliation: Medicines for Malaria Venture, 20 Route de Pré-Bois, 1215 Geneva 15, Switzerland.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Burrows
authors.affiliation: 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.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Davioud-Charvet
authors.affiliation: Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen, Heinrich Buff Ring 26-32, 35392 Giessen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rahlfs
authors.affiliation: Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen, Heinrich Buff Ring 26-32, 35392 Giessen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Becker
mesh_terms: D000588:Amines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000852:Anopheles / Q000469:parasitology; D000890:Anti-Infective Agents / Q000494:pharmacology; D000977:Antiparasitic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005854:Germ Cells / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008018:Life Cycle Stages / Q000187:drug effects; D008288:Malaria / Q000469:parasitology / Q000635:transmission; D051379:Mice; D008954:Models, Biological; D010271:Parasites / Q000187:drug effects; D010962:Plasmodium berghei / Q000187:drug effects / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development; D012550:Schistosoma mansoni / Q000187:drug effects / Q000648:ultrastructure; D013256:Steroids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D023382:Toxicity Tests, Acute
chemical_list: D000588:Amines; D000890:Anti-Infective Agents; D000977:Antiparasitic Agents; D013256:Steroids