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) 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.