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

Abstract

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 β-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 magnetic 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 Arabidopsis thaliana HPPD (AtHPPD) verified that compound II-3 showed the most activity with an IC50 value of 0.248 μM, which was superior to that of mesotrione (0.283 μM) 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.