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The protein is an attractive target for the development of anti\u2010infectives and herbicides. Using a photometric assay, a screen of 40\u2009000 compounds on IspF from <jats:italic>Arabidopsis thaliana<\/jats:italic> afforded symmetrical aryl bis\u2010sulfonamides that inhibit IspF from <jats:italic>A.\u2005thaliana<\/jats:italic> (<jats:italic>At<\/jats:italic>IspF) and <jats:italic>Plasmodium falciparum<\/jats:italic> (<jats:italic>Pf<\/jats:italic>IspF) with IC<jats:sub>50<\/jats:sub> values in the micromolar range. The <jats:italic>ortho<\/jats:italic>\u2010bis\u2010sulfonamide structural motif is essential for inhibitory activity. The best derivatives obtained by parallel synthesis showed IC<jats:sub>50<\/jats:sub> values of 1.4\u2005\u03bc<jats:sc>m <\/jats:sc>against <jats:italic>Pf<\/jats:italic>IspF and 240\u2005n<jats:sc>m <\/jats:sc>against <jats:italic>At<\/jats:italic>IspF. Substantial herbicidal activity was observed at a dose of 2\u2005kg\u2009ha<jats:sup>\u22121<\/jats:sup>. Molecular modeling studies served as the basis for an in silico search targeted at the discovery of novel, non\u2010symmetrical sulfonamide IspF inhibitors. 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