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

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

来源：ChemMedChem, 2015, 10(12): 2090-2098.

DOI：10.1002/cmdc.201500382

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

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 40000 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 1.4m against PfIspF and 240nm against AtIspF. Substantial herbicidal activity was observed at a dose of 2kgha(-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.

• 出版日期2015-12