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Background In recent years, protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors have been widely studied as important agricultural herbicides. Our research effort was focused on the design and synthesis of novel PPO inhibitor herbicides, done through the linking of a diphenylether pyridine bioisostere structure to substituted coumarins, which aims to enhance environmental and crop safety while retaining high efficacy. The work done in our research are the design and synthesize of a series of phenoxypyridine derivatives. Results In this work, a total of 21 compounds were synthesized via acylation reactions and all the compounds were characterized using IR, 1 H-NMR, 13 C-NMR, and high-resolution mass spectra. The respective configuration of compound 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, especially compound IV-6 which displayed better herbicidal activity in greenhouse and field experiments, crop selectivity and safety for cotton and soybean as compared to that of the commercial herbicide oxyfluorfen. Conclusion The present work revealed that the compound IV-6 deserves further attention as the candidate structure of novel and safe herbicide. This article is protected by copyright. All rights reserved.

Protoporphyrinogen oxidase (PPO) is an important target for discovering new herbicides that interfere with the synthesis of porphyrin. To discover new PPO inhibitors with improved biological activity, a series of new diphenyl ethers containing tetrahydrophthalimide were 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 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 ai ha−1, 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 the mechanism of action of J6.3. The results show that the introduction of a nitro group and tetrahydrophthalimide into the diphenyl ether structure is beneficial to biological activity.

To seek novel and safe protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors with excellent herbicidal activity. A series of novel phenoxypyridine derivatives containing natural product coumarins with allelopathy were designed and synthesized based on bioisosterism and active subunit combination in this research. Compounds W3.1 and W3.4, with the half-maximal inhibitory concentration (IC50) value of 0.02653 mg/L and 0.01937 mg/L, respectively, displayed excellent herbicidal activity in greenhouse. Their herbicidal activity was similar to commercial herbicide oxyfluorfen (IC50 = 0.04943 mg/L). The best field inhibitory effect of compounds W3.1 and W3.4 recorded was at doses of 450 g ai/ha and 300 g ai/ha, respectively. Compound W3.4 had the best herbicidal activity among all the target compounds in this paper. Molecular docking analysis revealed that compounds W3.1 and W3.4 could form a hydrogen bonds with the amino acid AGR-98 and a π-π superposition with the amino acid PHE-398, respectively, which was similar to the oxyfluorfen. The crop selectivity tests results indicated that maize, cotton and soybean showed high tolerance to compound W3.4. Compound W3.4 reduced the Ca and Cb contents of wheat and rice, but had less effect on maize, cotton and soybean. Selectivity of compound W3.4 in maize, cotton and soybean were appeared to be due to reduced absorption of the herbicide compared to wheat and rice. Compound W3.4 deserves further attention as a candidate structure for new herbicides.

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

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&ndash, 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&middot, kg&minus, 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.

As important chemical pesticides, protoporphyrinogen oxidase (PPO, EC 1.3.3.4) herbicides play a vital role in weed management. Herein, in a search for novel PPO herbicides, a series of phenoxypyridine-2-pyrrolidinone derivatives were synthesized and their herbicidal activities were tested. To confirm the structures of the newly synthesized compounds, a colorless single crystal of compound 9d was obtained and crystallographic data collected. PPO inhibition experiments showed that most compounds have PPO inhibitory effects. The half-maximal inhibitory concentration (IC50) of compound 9d and oxyfluorfen were 0.041 mg/L and 0.043 mg/L, respectively, which showed compound 9d was the most potent compound. Compound 9d reduced the Chlorophyll a (Chl a) and Chlorophyll b (Chl b) contents of Abutilon theophrasti (A. theophrasti), to 0.306 and 0.217 mg/g, respectively. Crop selectivity experiments and field trial indicated that compound 9d can potentially be used to develop post-emergence herbicides for weed control in rice, cotton, and peanut. Molecular docking studies showed that both oxyfluorfen and compound 9d can enter the PPO cavity to occupy the active site and compete with the porphyrin to block the chlorophyll synthesis process, affect photosynthesis, and eventually cause weed death. Compound 9d was found to be a promising lead compound for novel herbicide development.

C17H20ClNO3S, orthorhombic, P212121 (no. 19), a = 6.1984(2) Å, b = 14.3940(5) Å, c = 18.9651(6) Å, V = 1692.06(10) Å3, Z = 4, R gt(F) = 0.0263, wR ref(F 2) = 0.0683, T = 293(2) K.