Tembotrione, a 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor, has been widely used in many types of plants. Tembotrione has been reported for its likelihood of causing injury and plant death to certain corn hybrids. Safeners are co-applied with herbicides to protect certain crops without compromising weed control efficacy. Alternatively, herbicide safeners may effectively improve herbicide selectivity. To address tembotrione-induced Zea mays injury, a series of novel ester-substituted cyclohexenone derivatives were designed using the fragment splicing method. In total, 35 title compounds were synthesized via acylation reactions. All the compounds were characterized using infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. The configuration of compound II-15 was confirmed using single-crystal X-ray diffraction. The bioactivity assay proved that tembotrione phytotoxicity to maize could be reduced by most title compounds. In particular, compound II-14 exhibited the highest activity against tembotrione. The molecular structure comparisons as well as absorption, distribution, metabolism, excretion, and toxicity predictions demonstrated that compound II-14 exhibited pharmacokinetic properties similar to those of the commercial safener isoxadifen-ethyl. The molecular docking model indicated that compound II-14 could prevent tembotrione from reaching or acting with Z. mays HPPD (PDB: 1SP8). Molecular dynamics simulations showed that compound II-14 maintained satisfactory stability with Z. mays HPPD. This research revealed that ester-substituted cyclohexenone derivatives can be developed as potential candidates for discovering novel herbicide safeners in the future.

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Nicosulfuron is the leading herbicide in the global sulfonylurea (SU) herbicide market; it was jointly developed by DuPont and Ishihara. Recently, the widespread use of nicosulfuron has led to increasingly prominent agricultural production hazards, such as environmental harm and influence on subsequent crops. The use of herbicide safeners can significantly alleviate herbicide injury to protect crop plants and expand the application scope of existing herbicides. A series of novel aryl-substituted formyl oxazolidine derivatives were designed using the active group combination method. Title compounds were synthesized using an efficient one-pot method and characterized by infrared (IR) spectrometry, 1H and 13C nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HRMS). The chemical structure of compound V-25 was further identified by X-ray single crystallography. The bioactivity assay and structure–activity relationship proved that nicosulfuron phytotoxicity to maize could be reduced by most title compounds. The glutathione S-transferase (GST) activity and acetolactate synthase (ALS) in vivo were determined, and compound V-12 showed inspiring activity comparable to that of the commercial safener isoxadifen-ethyl. The molecular docking model indicated that compound V-12 competed with nicosulfuron for the acetolactate synthase active site and that this is the protective mechanism of safeners. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions demonstrated that compound V-12 exhibited superior pharmacokinetic properties to the commercialized safener isoxadifen-ethyl. The target compound V-12 shows strong herbicide safener activity in maize; thus, it may be a potential candidate compound that can help further protect maize from herbicide damage.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a pivotal enzyme in tocopherol and plastoquinone synthesis and a potential target for novel herbicides. Thirty-five pyridine derivatives were selected to establish a Topomer comparative molecular field analysis (Topomer CoMFA) model to obtain correlation information between HPPD inhibitory activity and the molecular structure. A credible and predictive Topomer CoMFA model was established by “split in two R-groups” cutting methods and fragment combinations (q2 = 0.703, r2 = 0.957, ONC = 6). The established model was used to screen out more active compounds and was optimized through the auto in silico ligand directing evolution (AILDE) platform to obtain potential HPPD inhibitors. Twenty-two new compounds with theoretically good HPPD inhibition were obtained by combining the high-activity contribution substituents in the existing molecules with the R-group search via Topomer search. Molecular docking results revealed that most of the 22 fresh compounds could form stable π-π interactions. The absorption, distribution, metabolism, excretion and toxicity (ADMET) prediction and drug-like properties made 9 compounds potential HPPD inhibitors. Molecular dynamics simulation indicated that Compounds Y12 and Y14 showed good root mean square deviation (RMSD) and root mean square fluctuation (RMSF) values and stability. According to the AILDE online verification, 5 new compounds with potential HPPD inhibition were discovered as HPPD inhibitor candidates. This study provides beneficial insights for subsequent HPPD inhibitor design.

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BACKGROUND 4‐Hydroxyphenylpyruvate dioxygenase (HPPD) herbicides control broadleaf and gramineous weeds with better crop safety for corn, sorghum and wheat. Multiple screening models in silico have been established to obtain novel lead compounds as HPPD inhibition herbicides. RESULTS Topomer comparative molecular field analysis (CoMFA) combined with topomer search technology and Bayesian, genetic approximation functions (GFA) and multiple linear regression (MLR) models generated by calculating different descriptors were constructed for the quinazolindione derivatives of HPPD inhibitors. The coefficient of determination (r2) of topomer CoMFA, MLR and GFA were 0.975, 0.970 and 0.968, respectively; all the models established displayed excellent accuracy and high predictive capacity. Five compounds with potential HPPD inhibition were obtained via screening fragment library combined with the validation of the above models and molecular docking studies. After molecular dynamics (MD) validation and absorption, distribution, metabolism, excretion and toxicity (ADMET) prediction, the compound 2‐(2‐amino‐4‐(4H‐1,2,4‐triazol‐4‐yl) benzoyl)‐3‐hydroxycyclohex‐2‐en‐1‐one not only exhibited stable interactions with the protein but also high solubility and low toxicity, and has potential as a novel HPPD inhibition herbicide. CONCLUSION In this study, five compounds were obtained through multiple quantitative structure–activity relationship screening. Molecular docking and MD experiments showed that the constructed approach had good screening ability for HPPD inhibitors. This work provided molecular structural information for developing novel, highly efficient and low‐toxicity HPPD inhibitors. © 2023 Society of Chemical Industry.

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