ABSTRACT
4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a crucial target enzyme in albino herbicides. The inhibition of HPPD activity interferes with the synthesis of carotenoids, blocking photosynthesis and resulting in bleaching and necrosis. To develop herbicides with excellent activity, a series of 3-hydroxy-2-(6-substituted phenoxynicotinoyl)-2-cyclohexen-1-one derivatives were designed via active substructure combination. The title compounds were characterized via infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopies, and high-resolution mass spectrometry. The structure of compound III-17 was confirmed via single-crystal X-ray diffraction. Preliminary tests demonstrated that some compounds had good herbicidal activity. Crop safety tests revealed that compound III-29 was safer than the commercial herbicide mesotrione in wheat and peanuts. Moreover, the compound exhibited the highest inhibitory activity against Arabidopsis thaliana HPPD (AtHPPD), with a half-maximal inhibitory concentration of 0.19 µM, demonstrating superior activity compared with mesotrione (0.28 µM) in vitro. A three-dimensional quantitative structure-activity relationship study revealed that the introduction of smaller groups to the 5-position of cyclohexanedione and negative charges to the 3-position of the benzene ring enhanced the herbicidal activity. A molecular structure comparison demonstrated that compound III-29 was beneficial to plant absorption and conduction. Molecular docking and molecular dynamics simulations further verified the stability of the complex formed by compound III-29 and AtHPPD. Thus, this study may provide insights into the development of green and efficient herbicides.
Subject(s)
4-Hydroxyphenylpyruvate Dioxygenase , Arabidopsis , Drug Design , Enzyme Inhibitors , Herbicides , Molecular Docking Simulation , Herbicides/chemistry , Herbicides/pharmacology , Herbicides/chemical synthesis , 4-Hydroxyphenylpyruvate Dioxygenase/antagonists & inhibitors , 4-Hydroxyphenylpyruvate Dioxygenase/chemistry , 4-Hydroxyphenylpyruvate Dioxygenase/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Arabidopsis/drug effects , Arabidopsis/growth & development , Structure-Activity Relationship , Molecular Structure , Ketones/chemistry , Ketones/pharmacology , Ketones/chemical synthesis , Cyclohexanones/chemistry , Cyclohexanones/pharmacology , Cyclohexanones/chemical synthesis , Triticum/chemistry , Arabidopsis Proteins/antagonists & inhibitors , Arabidopsis Proteins/chemistry , Arabidopsis Proteins/metabolismABSTRACT
Cinnamic acid, isolated from cinnamon bark, is a natural product with excellent bioactivity, and it effectively binds with cyclohexanedione to form novel 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors. According to the active sub-structure combination principle, a series of novel 3-hydroxy-2-cinnamoyl-2-en-1-one derivatives were designed and synthesized. The title compounds were characterized by infrared, 1H NMR, 13C NMR, and HRMS. The in vitro inhibitory activity of AtHPPD verified that compound II-13 showed the most activity with a half-maximal inhibitory concentration (IC50) value of 0.180 µM, which was superior to that of mesotrione (0.206 µM) in vitro. The preliminary herbicidal activity tests demonstrated that some compounds had good herbicidal activity especially compound II-13 at a concentration of 150 g ai/ha. The binding mode of AtHPPD through molecular docking indicated that two oxygens of compounds II-13 formed bidentate interactions with metal ions, and the benzene ring formed π-π accumulation effects with Phe-381 and Phe-424. The results of molecular dynamics simulations showed that compound II-13 exhibited a more stable binding ability with AtHPPD than mesotrione. This study provided insights into the development of natural and efficient herbicides in the future.
