Design, Synthesis, and Herbicidal Activity of Novel Diketonitrile Derivatives as HPPD Inhibitors

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an attractive target for the development of bleaching herbicides. To develop novel HPPD inhibitors, 40 diketonitrile derivatives were designed by active-fragment splicing, synthesized, and characterized. In vitro inhibitory assays against Echinochloa crus-galli HPPD (EcHPPD) showed that compound III-2 exhibited the strongest activity, with a half-maximal inhibitory concentration (IC50) of 0.132 μM, outperforming mesotrione (0.277 μM). Preliminary bioassays demonstrated that compound III-2 had excellent herbicidal activity against E. crus-galli and Arabidopsis thaliana (AT) at a dose of 150 g a.i./ha. Crop safety evaluations revealed that compound III-2 was safer than the commercial herbicides mesotrione and isoxaflutole in sorghum and soybean. Molecular docking and molecular dynamics simulations revealed stable binding to HPPD, while electrostatic potential and density functional theory analyses demonstrated favorable electronic properties underlying its high activity. Compound III-2 represents a promising lead for developing novel HPPD-inhibiting diketonitrile herbicides.