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

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