title: Aryl Bis-Sulfonamide Inhibitors of IspF from Arabidopsis thaliana and Plasmodium falciparum.
abstract: 2-Methylerythritol 2,4-cyclodiphosphate synthase (IspF) is an essential enzyme for the biosynthesis of isoprenoid precursors in plants and many human pathogens. The protein is an attractive target for the development of anti-infectives and herbicides. Using a photometric assay, a screen of 40 000 compounds on IspF from Arabidopsis thaliana afforded symmetrical aryl bis-sulfonamides that inhibit IspF from A. thaliana (AtIspF) and Plasmodium falciparum (PfIspF) with IC50 values in the micromolar range. The ortho-bis-sulfonamide structural motif is essential for inhibitory activity. The best derivatives obtained by parallel synthesis showed IC50 values of 1.4 μm against PfIspF and 240 nm against AtIspF. Substantial herbicidal activity was observed at a dose of 2 kg ha(-1) . Molecular modeling studies served as the basis for an in silico search targeted at the discovery of novel, non-symmetrical sulfonamide IspF inhibitors. The designed compounds were found to exhibit inhibitory activities in the double-digit micromolar IC50 range.
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Jonas
authors.initials: J
authors.lastname: Thelemann
authors.affiliation: Institut für Lebensmittelchemie, Universität Hamburg, Grindelallee 117, 20146, Hamburg, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Illarionov
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Barylyuk
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Julie
authors.initials: J
authors.lastname: Geist
authors.affiliation: Zentrum für Bioinformatik, Universität Hamburg, Bundesstr. 43, 20146, Hamburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kirchmair
authors.affiliation: Institut für Pharmazeutische Wissenschaften, ETH Zürich, Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Schneider
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Lucile
authors.initials: L
authors.lastname: Anthore
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Root
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Nils
authors.initials: N
authors.lastname: Trapp
authors.affiliation: Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergerstr. 4, 85748, Garching, Germany.
authors.forename: Adelbert
authors.initials: A
authors.lastname: Bacher
authors.affiliation: BASF SE, Carl-Bosch-Str. 38, 67056, Ludwigshafen, Germany. matthias.witschel@basf.com.
authors.forename: Matthias
authors.initials: M
authors.lastname: Witschel
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland. diederich@org.chem.ethz.ch.
authors.forename: Renato
authors.initials: R
authors.lastname: Zenobi
authors.affiliation: Institut für Lebensmittelchemie, Universität Hamburg, Grindelallee 117, 20146, Hamburg, Germany. markus.fischer@chemie.uniso-hamburg.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Institut für Pharmazeutische Wissenschaften, ETH Zürich, Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland. gisbert.schneider@pharma.ethz.ch.
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland. zenobi@org.chem.ethz.ch.
authors.forename: François
authors.initials: F
authors.lastname: Diederich
mesh_terms: D017360:Arabidopsis / Q000201:enzymology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D019761:Phosphorus-Oxygen Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000201:enzymology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D013449:Sulfonamides; D019761:Phosphorus-Oxygen Lyases; C512265:IspF protein, Arabidopsis
keywords: P. falciparum; bis-sulfonamides; docking; inhibitors; isoprenoid biosynthesis; non-mevalonate pathway