Novel reverse thia-analogs of fosmidomycin: Synthesis and antiplasmodial activity

Claudia Lienau; Tobias Gräwert; Leandro A Alves Avelar; Boris Illarionov; Jana Held; Tanja C Knaab; Beate Lungerich; Lasse van Geelen; Dieter Meier; Stefanie Geissler; Holger Cynis; Ulrich Riederer; Mirko Buchholz; Rainer Kalscheuer; Adelbert Bacher; Benjamin Mordmüller; Markus Fischer; Thomas Kurz

doi:10.1016/j.ejmech.2019.07.058

Novel reverse thia-analogs of fosmidomycin: Synthesis and antiplasmodial activity

Eur J Med Chem. 2019 Nov 1:181:111555. doi: 10.1016/j.ejmech.2019.07.058. Epub 2019 Jul 22.

Authors

Claudia Lienau¹, Tobias Gräwert², Leandro A Alves Avelar¹, Boris Illarionov³, Jana Held⁴, Tanja C Knaab¹, Beate Lungerich¹, Lasse van Geelen⁵, Dieter Meier⁵, Stefanie Geissler⁶, Holger Cynis⁶, Ulrich Riederer⁷, Mirko Buchholz⁶, Rainer Kalscheuer⁵, Adelbert Bacher⁸, Benjamin Mordmüller⁴, Markus Fischer³, Thomas Kurz⁹

Affiliations

¹ Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany.
² Hamburg School of Food Science, University of Hamburg, Grindelallee 117, 20146, Hamburg, Germany; Hamburg Outstation, European Molecular Biology Laboratory, Notkestraße 85, 22607, Hamburg, Germany.
³ Hamburg School of Food Science, University of Hamburg, Grindelallee 117, 20146, Hamburg, Germany.
⁴ Institute of Tropical Medicine, University of Tübingen, Wilhelmstr. 27, 72074, Tübingen, Germany; Centre de Recherches Médicales de Lambaréné (CERMEL), Centre de Recherches Médicales de Lambaréné, B.P: 242, Lambaréné, Gabon.
⁵ Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany.
⁶ Fraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Weinbergweg 22, 06120, Halle (Saale), Germany.
⁷ Institute of Pharmacy, University of Hamburg, Bundesstr. 45, 20146, Hamburg, Germany.
⁸ Hamburg School of Food Science, University of Hamburg, Grindelallee 117, 20146, Hamburg, Germany; Department of Chemistry, Technical University of Munich, Lichtenbergstr. 4, D-85748, Garching, Germany.
⁹ Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany. Electronic address: thomas.kurz@uni-duesseldorf.de.

PMID: 31382119
DOI: 10.1016/j.ejmech.2019.07.058

Abstract

Thia analogs of fosmidomycin are potent inhibitors of the non-mevalonate isoprenoid biosynthesis enzyme 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC, Dxr) of Plasmodium falciparum. Several new thioethers displayed antiplasmodial in vitro activity in the low nanomolar range, without apparent cytotoxic effects in HeLa cells. The (S)-(+)-enantiomer of a typical representative selectively inhibited IspC and the growth of P. falciparum in continuous culture. The inhibitor was stable at pH 7.6 and room temperature, and no racemization was observed under these conditions during a period of up to two days. Oxidation of selected thioethers to sulfones reduced antiplasmodial activity and the inhibitory activity against Escherichia coli, Mycobacterium tuberculosis and P. falciparum IspC orthologs.

Keywords: Antiplasmodial activity; Enantioselectivity; Fosmidomycin thia isosters; IspC; Sulfones.

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Antiprotozoal Agents / chemical synthesis
Antiprotozoal Agents / chemistry
Antiprotozoal Agents / pharmacology*
Caco-2 Cells
Dose-Response Relationship, Drug
Escherichia coli / drug effects*
Escherichia coli / growth & development
Fosfomycin / analogs & derivatives*
Fosfomycin / chemical synthesis
Fosfomycin / chemistry
Fosfomycin / pharmacology
HeLa Cells
Humans
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / growth & development
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects*
Plasmodium falciparum / growth & development
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Antiprotozoal Agents
Fosfomycin
fosmidomycin