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.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is an important target for discovering novel herbicides, and it causes bleaching symptoms by inhibiting the synthesis of chlorophyll and heme. In this study, the active fragments of several commercial herbicides were joined by substructure splicing and bioisosterism, and a series of novel diphenyl ether derivatives containing fivemembered heterocycles were synthesized. The greenhouse herbicidal activity and the PPO inhibitory activity in vitro were discussed in detail. The results showed that most compounds had good PPO inhibitory activity, and target compounds containing trifluoromethyl groups tended to have higher activity. Among them, compound G4 showed the best inhibitory activity, with a halfmaximal inhibitory concentration (IC 50 ) of 0.0468 μmol/L, which was approximately 3 times better than that of oxyfluorfen (IC 50 = 0.150 μmol/L). In addition, molecular docking indicated that compound G4 formed obvious π−π stacking interactions and hydrogen bond interactions with PHE-392 and ARG-98, respectively. Remarkably, compound G4 had good safety for corn, wheat, rice, and soybean, and the cumulative concentration in crops was lower than that of oxyfluorfen. Therefore, compound G4 can be used to develop potential lead compounds for novel PPO inhibitors.

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The herbicide fomesafen has the advantages of low toxicity and high selectivity, and the target of this compound is protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4). However, this herbicide has a long residual period and can have phytotoxic effects on succeeding crops. To protect maize from fomesafen, a series of thiazole phenoxypyridines were designed based on structure–activity relationships, active substructure combinations, and bioisosterism. Bioassays showed that thiazole phenoxypyridines could improve maize tolerance under fomesafen toxicity stress to varying degrees at a dose of 10 mg·kg−1. Compound 4i exhibited the best effects. After being treated by compound 4i, average recovery rates of growth index exceeded 72%, glutathione content markedly increased by 167% and glutathione S-transferase activity was almost 163% of fomesafen-treated group. More importantly, after being treated by compound 4i, the activity of PPO, the main target enzyme of fomesafen, recovered to 93% of the control level. The molecular docking result exhibited that the compound 4i could compete with fomesafen to bind with the herbicide target enzyme, which consequently attained the herbicide detoxification. The present work suggests that compound 4i could be developed as a potential safener to protect maize from fomesafen.

Protoporphyrinogen oxidase (PPO) is an important target for discovering new herbicides that interfere with the synthesis of porphyrin. In order to discover new PPO inhibitor herbicides with improved biological activity, a series of new diphenyl ethers containing tetrahydrophthalimide are designed and synthesized. Among them, J6.1 (IC50=4.7 nM) and J6.3 (IC50=30.0 nM) show higher maize (Zea mays L.)PPO inhibitory activity than the commercial herbicides, i.e., oxyfluorfen (IC50=117.9 nM) and flumioxazin (IC50=157.1 nM). The greenhouse herbicidal activity of J6.3 is comparable to that of oxyfluorfen, and it is greater than that of flumioxazin. Even at a dose of 300 g active ingredients/hectare (a.i/ha), cotton (Gossypium hirsutum L.) and peanut (Arachis hypogaea L.) show greater tolerance to J6.3, suggesting that J6.3 could be used for further development of new herbicide candidates in those fields. In addition, molecular docking has been used to further study its mechanism of action. The results show that the introduction of nitro group and tetrahydrophthalimide into the diphenyl ether structure is beneficial to biological activity.

BACKGROUND In recent years, protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors have been widely studied as important agricultural herbicides. Our research focused on the design and synthesis of novel PPO inhibitor herbicides, through linking of a diphenylether pyridine bioisostere structure to substituted coumarins, which aims to enhance environmental and crop safety while retaining high efficacy. RESULTS A total of 21 compounds were synthesized via acylation reactions and all compounds were characterized using infrared, 1H NMR, 13C NMR, and high‐resolution mass spectra. The respective configurations of compounds IV‐6 and IV‐12 were also confirmed using single crystal X‐ray diffraction. The bioassay results showed that the title compounds displayed notable herbicidal activity, particularly compound IV‐6 which displayed better herbicidal activity in greenhouse and field experiments, crop selectivity and safety for cotton and soybean compared with the commercial herbicide oxyfluorfen. CONCLUSION The work revealed that compound IV‐6 deserves further attention as a candidate structure for a novel and safe herbicide. © 2021 Society of Chemical Industry.

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