Aryl Bis-Sulfonamide Inhibitors of IspF from Arabidopsis thaliana and Plasmodium falciparum

Jonas Thelemann; Boris Illarionov; Konstantin Barylyuk; Julie Geist; Johannes Kirchmair; Petra Schneider; Lucile Anthore; Katharina Root; Nils Trapp; Adelbert Bacher; Matthias Witschel; Renato Zenobi; Markus Fischer; Gisbert Schneider; Francois Diederich

doi:10.1002/cmdc.201500382

Aryl Bis-Sulfonamide Inhibitors of IspF from Arabidopsis thaliana and Plasmodium falciparum

Jonas Thelemann, Boris Illarionov, Konstantin Barylyuk, Julie Geist, Johannes Kirchmair, Petra Schneider, Lucile Anthore, Katharina Root, Nils Trapp, Adelbert Bacher, Matthias Witschel, Renato Zenobi, Markus Fischer, Gisbert Schneider, Francois Diederich

Publications: Contribution to journal › Article › Peer Reviewed

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 IC ₅₀ values in the micromolar range. The ortho-bis-sulfonamide structural motif is essential for inhibitory activity. The best derivatives obtained by parallel synthesis showed IC ₅₀ 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 IC ₅₀ range.

Original language	English
Pages (from-to)	2090-2098
Number of pages	9
Journal	ChemMedChem
Volume	10
Issue number	12
DOIs	https://doi.org/10.1002/cmdc.201500382
Publication status	Published - 2015

Austrian Fields of Science 2012

106005 Bioinformatics
301207 Pharmaceutical chemistry

Keywords

bis-sulfonamides
docking
inhibitors
isoprenoid biosynthesis
non-mevalonate pathway
P. falciparum
P. falciparum

Access to Document

10.1002/cmdc.201500382

Cite this

Thelemann, J., Illarionov, B., Barylyuk, K., Geist, J., Kirchmair, J., Schneider, P., Anthore, L., Root, K., Trapp, N., Bacher, A., Witschel, M., Zenobi, R., Fischer, M., Schneider, G., & Diederich, F. (2015). Aryl Bis-Sulfonamide Inhibitors of IspF from Arabidopsis thaliana and Plasmodium falciparum. ChemMedChem, 10(12), 2090-2098. https://doi.org/10.1002/cmdc.201500382

@article{48ba4611d2174a9ea1e09a33ca11348a,

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 IC 50 values in the micromolar range. The ortho-bis-sulfonamide structural motif is essential for inhibitory activity. The best derivatives obtained by parallel synthesis showed IC 50 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 IC 50 range. ",

keywords = "bis-sulfonamides, docking, inhibitors, isoprenoid biosynthesis, non-mevalonate pathway, P. falciparum, P. falciparum",

author = "Jonas Thelemann and Boris Illarionov and Konstantin Barylyuk and Julie Geist and Johannes Kirchmair and Petra Schneider and Lucile Anthore and Katharina Root and Nils Trapp and Adelbert Bacher and Matthias Witschel and Renato Zenobi and Markus Fischer and Gisbert Schneider and Francois Diederich",

note = "Publisher Copyright: {\textcopyright} 2015 Wiley-VCH Verlag GmbH \& Co. KGaA, Weinheim.",

year = "2015",

doi = "10.1002/cmdc.201500382",

language = "English",

volume = "10",

pages = "2090--2098",

journal = "ChemMedChem",

issn = "1860-7179",

publisher = "WILEY-V C H VERLAG GMBH",

number = "12",

}

Thelemann, J, Illarionov, B, Barylyuk, K, Geist, J, Kirchmair, J, Schneider, P, Anthore, L, Root, K, Trapp, N, Bacher, A, Witschel, M, Zenobi, R, Fischer, M, Schneider, G & Diederich, F 2015, 'Aryl Bis-Sulfonamide Inhibitors of IspF from Arabidopsis thaliana and Plasmodium falciparum', ChemMedChem, vol. 10, no. 12, pp. 2090-2098. https://doi.org/10.1002/cmdc.201500382

TY - JOUR

T1 - Aryl Bis-Sulfonamide Inhibitors of IspF from Arabidopsis thaliana and Plasmodium falciparum

AU - Thelemann, Jonas

AU - Illarionov, Boris

AU - Barylyuk, Konstantin

AU - Geist, Julie

AU - Kirchmair, Johannes

AU - Schneider, Petra

AU - Anthore, Lucile

AU - Root, Katharina

AU - Trapp, Nils

AU - Bacher, Adelbert

AU - Witschel, Matthias

AU - Zenobi, Renato

AU - Fischer, Markus

AU - Schneider, Gisbert

AU - Diederich, Francois

PY - 2015

Y1 - 2015

N2 - 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 IC 50 values in the micromolar range. The ortho-bis-sulfonamide structural motif is essential for inhibitory activity. The best derivatives obtained by parallel synthesis showed IC 50 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 IC 50 range.

AB - 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 IC 50 values in the micromolar range. The ortho-bis-sulfonamide structural motif is essential for inhibitory activity. The best derivatives obtained by parallel synthesis showed IC 50 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 IC 50 range.

KW - bis-sulfonamides

KW - docking

KW - inhibitors

KW - isoprenoid biosynthesis

KW - non-mevalonate pathway

KW - P. falciparum

UR - https://www.scopus.com/pages/publications/84949745572

U2 - 10.1002/cmdc.201500382

DO - 10.1002/cmdc.201500382

M3 - Article

SN - 1860-7179

VL - 10

SP - 2090

EP - 2098

JO - ChemMedChem

JF - ChemMedChem

IS - 12

ER -

Aryl Bis-Sulfonamide Inhibitors of IspF from Arabidopsis thaliana and Plasmodium falciparum

Abstract

Austrian Fields of Science 2012

Keywords

Access to Document

Other files and links

Fingerprint

Cite this