Chemical Synthesis, Herbicidal Activity, Crop Safety,\nand Molecular Basis of <i>ortho</i>-Fluoroalkoxy Substituted\nSulfonylureas as Novel Acetohydroxyacid Synthase Inhibitors

In\nthe face of increasing resistance to the currently used commercial\nherbicides and the lack of success in identifying new herbicide targets,\nalternative herbicides need to be developed to control unwanted monocotyledon\ngrasses in food crops. Here, a panel of 29 novel sulfonylurea-based\ncompounds with <i>ortho-</i>fluoroalkoxy substitutions at\nthe phenyl ring were designed and synthesized. Pot assays demonstrated\nthat two of these compounds, <b>6d</b> and <b>6u</b>,\nhave strong herbicidal activities against Echinochloa\ncrus-galli, Eleusine indica, Alopecurus aequalis, and Alopecurus japonicus Steudel at a dosage of 15 g\nha<sup>–1</sup>. Furthermore, these two compounds exhibited\n<5% inhibition against wheat at a dosage of 30 g ha<sup>–1</sup> under post-emergence conditions. <b>6u</b> also exhibited\n<5% inhibition against rice at a dosage of 30 g ha<sup>–1</sup> under both post-emergence and pre-emergence conditions. A kinetics\nstudy demonstrated that <b>6d</b> and <b>6u</b> are potent\ninhibitors of Arabidopsis thaliana acetohydroxyacid\nsynthase (AHAS; EC 2.2.1.6) with potent <i>K<sub>i</sub></i> values of 18 ± 1.1 and 11.9 ± 4.0 nM, respectively. The\ncrystal structure of <b>6u</b> in complex with A. thaliana (<i>At</i>)AHAS has also been\ndetermined at 2.7 Å resolution. These new compounds represent\nnew alternative herbicide choices to protect wheat or rice from invading\ngrasses.