Design, synthesis and biological activity of novel triketone herbicides containing natural product fragments

4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) belongs to the non-heme Fe2+ -containing enzyme family and is an important enzyme in tyrosine decomposition. HPPD is crucial to the discovery of novel bleaching herbicides. To develop novel HPPD inhibitor herbicides containing the & beta;-triketone motif, a series of 4-hydroxyl-3-(substituted aryl)-pyran-2-one derivatives were designed using the active fragment splicing method. The title compounds were synthesized and characterized through infrared spectroscopy (IR), 1H nuclear mag-netic resonance (1H NMR), 13C nuclear magnetic resonance (13C NMR), and high-resolution mass spectrometry (HRMS). The X-ray diffraction method determined the single crystal structure of I-17. Preliminary bioassay data revealed that several novel compounds, especially I-12 and II-3, showed excellent herbicidal activity against broadleaf and monocotyledonous weeds at a dose of 150 g ai/ha. The results of crop selectivity and carotenoids determination indicated that compound I-12 is more suitable for wheat and cotton fields than mesotrione. Additionally, compound II-3 is safer for soybeans and peanuts than mesotrione. The inhibitory activity of Ara-bidopsis thaliana HPPD (AtHPPD) verified that compound II-3 showed the most activity with an IC50 value of 0.248 & mu;M, which was superior to that of mesotrione (0.283 & mu;M) in vitro. The binding mode of compound II-3 and AtHPPD was confirmed through molecular docking and molecular dynamics simulations. This study provides insights into the future development of natural and efficient herbicides.