Design, Synthesis, and Bioactivity of Novel 2-(Arylformyl)cyclohexane-1,3-dione Derivatives as HPPD Inhibitors.

4-Hydroxyphenylpyruvate dioxygenase inhibitors ( 1.13.11.27, HPPD) have gained significant popularity as one of the best-selling herbicides worldwide. To identify highly effective HPPD inhibitors, a rational design approach utilizing bioisosterism was employed to create a series of 2-(arylformyl)cyclohexane-1,3-dione derivatives. A total of 29 novel compounds were synthesized and characterized through various techniques, including IR, H NMR, C NMR, and HRMS. Evaluation of their inhibitory activity against HPPD (HPPD) revealed that certain derivatives exhibited superior potency compared to mesotrione (IC = 0.204 μM). Initial herbicidal activity tests demonstrated that compounds and were comparable to mesotrione in terms of weed control and crop safety, with compound exhibiting enhanced safety in canola crops. Molecular docking analyses indicated that the quinoline rings of compounds and formed more stable π-π interactions with the amino acid residues Phe-360 and Phe-403 in the active cavity of HPPD, surpassing the benzene ring of mesotrione. Molecular dynamics simulations and molecular structure comparisons confirmed the robust binding capabilities of compounds and to HPPD. This study provides a valuable reference for the development of novel triketone herbicide structures, serving as a blueprint for future advancements in this field.