4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is an important target site for discovering new bleaching herbicides. To explore novel HPPD inhibitors with excellent herbicidal activity, a series of novel N-aroyl diketone/ triketone derivatives were rationally designed by splicing active groups and bioisosterism. Bioassays revealed that most of these derivatives displayed preferable herbicidal activity against Echinochloa crus-galli (EC) at 0.045 mmol/m 2 and Abutilon juncea (AJ) at 0.090 mmol/m 2 . In particular, compound I-f was more potent compared to the commercialized compound mesotrione. Molecular docking indicated that the corresponding active molecules of target compounds and mesotrione shared similar interplay with surrounding residues, which led to a perfect interaction with the active site of Arabidopsis thaliana HPPD.

Tribenuron-methyl (TM), as one of the sulfonylurea (SU) herbicides, has been widely and effectively applied for many kinds of plants. SUs inhibit plant growth by restraining the biosynthetic pathway of branched-chain amino acids (BCAAs) catalyzed by acetolactate synthase (ALS). Safeners are agrochemicals that protect crops from herbicide injuries. To improve the crop tolerance under TM toxicity stress, this paper evaluated the protective effect of N-tosyloxazolidine-3-carboxamide. It turned out that most of the tested compounds showed significant protection against TM via enhancing the glutathione (GSH) content and glutathione S-transferase (GST) activity. Among all of the tested compounds, compound 16 exhibited more excellent protection than the contrast safener R-28725 and other target compounds. A positive correlation between the growth level, endogenous GSH content, and GST activity was observed in this research. The GST kinetic parameter V max of the maize was increased by 29.6% after treatment with compound 16, while K m was decreased by 51.9% compared to the untreated control. The molecular docking model indicated that compound 16 could compete with TM in the active site of ALS, which could interpret the protective effects of safeners. The present work demonstrated that N-tosyloxazolidine-3-carboxamide derivatives could be considered as potential candidates for developing new safeners in the future.

Herbicide safeners selectively protect crops from herbicide damage without reducing the herbicidal efficiency on target weed species. The title compounds were designed by the intermediate derivatization approach and fragment splicing to exploit novel potential safeners. A total of 31 novel diazabicyclo derivatives were synthesized by the microwave-assistant method using isoxazole-4-carbonyl chloride and diazabicyclo derivatives. All synthetic compounds were confirmed by infrared, 1H and 13C nuclear magnetic resonance, and high-resolution mass spectrometry. The bioassay results demonstrated that most of the title compounds could reduce the nicosulfuron phytotoxicity on maize. The glutathione S-transferase (GST) activity in vivo was assayed, and compound 4(S15) revealed an inspiring safener activity comparable to commercialized safeners isoxadifen-ethyl and BAS-145138. The molecular docking model exhibited that the competition at the active sites of target enzymes between compound 4(S15) and nicosulfuron was investigated with respect to herbicide detoxification. The current work not only provided a powerful supplement to the intermediate derivatization approach and fragment splicing in design pesticide bioactive molecules but also assisted safener development and optimization.

To seek new protoporphyrinogen oxidase (PPO) inhibitors with better biological activity, a series of novel diphenyl ether derivatives containing tetrahydrophthalimide were designed based on the principle of substructure splicing and bioisomerization. PPO inhibition experiments exhibited that 6c is the most potential compound, with the half-maximal inhibitory concentration (IC50) value of 0.00667 mg/L, showing 7 times higher activity than Oxyfluorfen (IC50 = 0.0426 mg/L) against maize PPO and similar herbicidal activities to Oxyfluorfen in weeding experiments in greenhouses and field weeding experiments. In view of the inspected bioactivities, the structure–activity relationship (SAR) of this series of compounds was also discussed. Crop selection experiments demonstrate that compound 6c is safe for soybeans, maize, rice, peanuts, and cotton at a dose of 300 g ai/ha. Accumulation analysis experiments showed that the accumulation of 6c in some crops (soybeans, peanuts, and cotton) was significantly lower than Oxyfluorfen. Current work suggests that compound 6c may be developed as a new herbicide candidate in fields.

Herbicide safeners enhance herbicide detoxification in crops without reducing their herbicidal efficacy against target weeds. To alleviate maize injury caused by the sulfonylurea herbicide nicosulfuron, a series of 1,3-disubstituted imidazolidine or hexahydropyrimidine derivatives were rationally designed via bioisosterism and active subunit combinations. Thirty novel compounds were synthesized using an efficient one-pot method and low-cost raw materials and characterized by IR, 1H NMR, 13C NMR, and high-resolution mass spectrometer (HRMS). Bioactivity and structure–activity relationship (SAR) were evaluated for herbicide safeners tested against nicosulfuron injury. Most of the compounds effectively protected sensitive maize against nicosulfuron damage. The parent skeletons and substituents of the target compounds both substantially influenced their safener activity. Compound I-3 exhibited superior bioactivity compared to the safener isoxadifen-ethyl. Molecular docking simulations disclosed that compound I-3 competed with nicosulfuron for the acetolactate synthase active site and demonstrated that this is the protective mechanism of safeners. The target compound I-3 presented with strong herbicide safener activity in maize and is, therefore, a potential candidate for the development of a novel herbicide safener.

Fenoxaprop-p-ethyl (FE), a type of acetyl-CoA carboxylase (ACCase) inhibitor, has been extensively applied to a variety of crop plants. It can cause damage to wheat (Triticum aestivum) even resulting in the death of the crop. On the prerequisite of not reducing herbicidal efficiency on target weed species, herbicide safeners selectively protect crops from herbicide injury. Based on fragment splicing, a series of novel substituted pyrazole derivatives was designed to ultimately address the phytotoxicity to wheat caused by FE. The title compounds were synthesized in a one-pot way and characterized via infrared spectroscopy, 1 H nuclear magnetic resonance, 13 C nuclear magnetic resonance, and high-resolution mass spectrometry. The bioactivity assay proved that the FE phytotoxicity to wheat could be reduced by most of the title compounds. The molecular docking model indicated that compound IV-21 prevented fenoxaprop acid (FA) from reaching or acting with ACCase. The absorption, distribution, metabolism, excretion, and toxicity predictions demonstrated that compound IV-21 exhibited superior pharmacokinetic properties to the commercialized safener mefenpyr-diethyl. The current work revealed that a series of newly substituted pyrazole derivatives presented strong herbicide safener activity in wheat. This may serve as a potential candidate structure to contribute to the further protection of wheat from herbicide injury.

Detoxification plays an important role in herbicide action. Herbicide safeners selectively protect crops from herbicide injury without reducing the herbicidal efficiency against the target weeds. With the large-scale use of herbicides, herbicide safeners have been widely used in sorghum, wheat, rice, corn, and other crops. In recent years, an increasing number of unexpected new herbicide safeners have been designed. The varieties, structural characteristics, uses, and synthetic routes of commercial herbicide safeners are reviewed in this paper. The design ideas and structural characteristics of novel herbicide safeners are summarized, which provide a basis for the design of bioactive molecules as new herbicide safeners in the future.

BACKGROUND: Herbicide safeners mitigate crop damage without reducing herbicide efficacy. Here, the protective effects of phenoxyacetyl oxazolidine derivatives as potential safeners were evaluated with a view toward reducing injury caused by sulfonylurea herbicide nicosulfuron to sensitive maize varieties. RESULTS: Growth indices demonstrated that the bioactivity of compound 9 (N-phenoxyacety-2-methyl-2,4-diethyl-1,3-oxazolidine) was superior to that of R-28725 and all other compounds tested. Compound 9 induced endogenous glutathione and upregulated glutathione-S-transferase (GST) in maize. Thus, it could enhance maize tolerance to nicosulfuron. Compared with the untreated water control group, the maximum reaction rate of GST was increased by 37.62%, while the maximum velocity of GST was decreased by 61.93% after treatment with compound 9. Acetolactate synthase relative activity was significantly enhanced in the case of treatment with compound 9, indicating the excellent protective effects of compound 9 against nicosulfuron in maize. CONCLUSIONS: The present work demonstrates that phenoxyacetyl oxazolidine derivatives are potentially efficacious as herbicide safeners and merit further investigation.