PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
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2025
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IF 4
Shiling Liu,Siying Qin,Tengfei Zhang,Heng Zhang,Junqi Zhu,Xiaoli Li,Yuanfu Li,Feng Zhao
Flusulfinam is a novel chiral amide herbicide widely used for controlling annual weeds in rice paddies. However, the mechanism underlying their enantioselective herbicidal activity remain unclear. Herein, it was found that flusulfinam enantiomers, similar to typical HPPD inhibitor mesotrione, reduced chlorophyll a nd carotenoid levels, decreased HPPD enzyme activity, and upregulated gene expression. Additionally, homogentisate supplementation alleviated the bleaching symptoms caused by flusulfinam and all these results validate that flusulfinam is indeed an HPPD inhibitor. To further investigate the mechanism of enantioselectivity, molecular docking was used and showed that R -flusulfinam (−6.55 kcal/mol) had higher binding energy than S- flusulfinam (−5.60 kcal/mol), due to more stable hydrogen bonds with Gln293. After mutating Gln293 to His, the IC 50 values for R -flusulfinam and S -flusulfinam on Mut Q293H were 0.73 mg/L and 0.11 mg/L, respectively, indicating swapped enantioselective inhibition compared to At HPPD, with IC 50 values of 0.52 mg/L and 1.93 mg/L, respectively. The Microscale Thermophoresis assay further revealed that the dissociation constant (Kd) for Mut Q293H with R -flusulfinam was 20.40 ± 4.19 μM, similar to the Kd value of 15.63 ± 4.51 μM for S -flusulfinam. The findings reveal that mutation of the Gln293 residue in the At HPPD enzyme significantly altered its enantioselective inhibition by flusulfinam. This study is the first to verify the mode of action of flusulfinam and identifies that Gln293 may play a key role in flusulfinam enantioselectivity in the At HPPD, laying the foundation for future HPPD inhibitor development based on flusulfinam.
研究领域:
植物生理学
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分子生物学
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农药科学
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产品关联
DOI
PubMed
高影响因子
INDUSTRIAL CROPS AND PRODUCTS
·
2019
·
IF 4.191
Ying Fu,Shuai-Qi Zhang,Yong-Xuan Liu,Jing-Yi Wang,Shuang Gao,Li-Xia Zhao,Fei Ye
4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is a very important target for the discovery of novel bleaching herbicides. In order to discover novel triketone green HPPD inhibitors with excellent herbicidal activity and crop selectivity, the natural product leptospermone was selected as the template compound, and niacin was employed as bioisostere to design and synthesize a series of novel substituted niacin-triketone derivatives. Some of the target compounds showed potent Arabidopsis thaliana HPPD ( At HPPD) inhibitory activity in vitro . Especially compound II-1 displayed the best herbicidal activity (IC 50 = 0.262 μM, At HPPD), and was safe for Zea mays at concentration of 300 g ai/ha. Molecular docking results indicated that the triketone moiety of compound II-1 could form a bidentate complex with Fe(II), and the pyridine subunit interacted with Phe430 and Phe360 via π−π packing. The present work indicated that 3-hydroxy-2-nicotinoylcyclohex-2-en-1-one could be a potential lead structure for developing novel green HPPD inhibitors.
研究领域:
植物学
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药物化学
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农业科学
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DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Jin Dong,Yi-Xuan Fu,Bai-Feng Zheng,Meng-Xi Chen,Qiong Chen,Kandegama Wishwajith,Jiangqing Dong,Hong-Yan Lin,Guang-Fu Yang
Mosquito-borne diseases remain a significant global health burden, necessitating innovative vector control strategies. 4-Hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors, widely used as herbicides, have been recently explored for their potential to disrupt mosquito tyrosine metabolic pathways, offering a novel approach to mosquito control. This study utilized a structure-based rational design strategy to repurpose existing HPPD inhibitors, such as pyrazole-benzene 2,2-dioxothiadiazole and pyrazole-1,3-isoindolinone hybrids, targeting Aedes aegypti HPPD ( Aa HPPD). Biochemical assays demonstrated that a series of synthesized hybrid compounds exhibited superior inhibitory activity against mosquito-derived HPPD compared to traditional inhibitors, the IC 50 values of compound a9 and compound c14 are 7.70 nM and 53.80 nM, respectively. Crystallographic analysis showed stable inhibitor binding mediated by chelation with metal ions in the active site and π-π interactions with Phe336 and Phe364. C6/36 cell assays further confirmed elevated tyrosine accumulation and significantly affected energy metabolism in the tricarboxylic acid cycle following treatment with the newly designed inhibitors. These findings highlight the potential of repurposed HPPD inhibitors as safe and effective mosquito control agents with novel mechanisms of action.
研究领域:
医学
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生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2021
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IF 5.279
Jia-Xu Nan,Jing-Fang Yang,Hong-Yan Lin,Yao-Chao Yan,Shao-Meng Zhou,Xue-Fang Wei,Qiong Chen,Wen-Chao Yang,Ren-Yu Qu,Guang-Fu Yang
Exploring novel p-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) inhibitors has become one of the most promising research directions in herbicide innovation. On the basis of our tremendous interest in exploiting more powerful HPPD inhibitors, we designed a family of benzyl-containing triketone-aminopyridines via a structure-based drug design (SBDD) strategy and then synthesized them. Among these prepared derivatives, the best active 3-hydroxy-2-(3,5,6-trichloro-4-((4-isopropylbenzyl)amino)picolinoyl)cyclohex-2-en-1-one (23, IC50 = 0.047 μM) exhibited a 5.8-fold enhancement in inhibiting Arabidopsis thaliana (At) HPPD activity over that of commercial mesotrione (IC50 = 0.273 μM). The predicted docking models and calculated energy contributions of the key residues for small molecules suggested that an additional π–π stacking interaction with Phe-392 and hydrophobic contacts with Met-335 and Pro-384 were detected in AtHPPD upon the binding of the best active compound 23 compared with that of the reference mesotrione. Such a molecular mechanism and the resulting binding affinities coincide with the proposed design scheme and experimental values. It is noteworthy that inhibitors 16 (3-hydroxy-2-(3,5,6-trichloro-4-((4-chlorobenzyl)amino)picolinoyl)cyclohex-2-en-1-one), 22 (3-hydroxy-2-(3,5,6-trichloro-4-((4-methylbenzyl)amino)picolinoyl)cyclohex-2-en-1-one), and 23 displayed excellent greenhouse herbicidal effects at 150 g of active ingredient (ai)/ha after postemergence treatment. Furthermore, compound 16 showed superior weed-controlling efficacy against Setaria viridis (S. viridis) versus that of the positive control mesotrione at multiple test dosages (120, 60, and 30 g ai/ha). These findings imply that compound 16, as a novel lead of HPPD inhibitors, possesses great potential for application in specifically combating the malignant weed S. viridis.
研究领域:
植物学
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药理学
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DOI
PubMed
高影响因子
PEST MANAGEMENT SCIENCE
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2021
·Vol. 78
·期 3
·938-946
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IF 4.845
Wei Hu,Shuang Gao,Li-Xia Zhao,Ke-Liang Guo,Jia-Yu Wang,Ying-Chao Gao,Xin-Xin Shao,Ying Fu,Fei Ye
BACKGROUND 4-Hydroxyphenyl pyruvate dioxygenase (EC 1.13.11.27, HPPD) is one of the important target enzymes used to address the issue of weed control. HPPD-inhibiting herbicides can reduce the carotenoid content in plants and hinder photosynthesis, eventually causing albinism and death. Exploring novel HPPD-inhibiting herbicides is a significant direction in pesticide research. In the process of exploring new high-efficiency HPPD inhibitors, a series of novel quinoxaline derivatives were designed and synthesized using an active fragment splicing strategy. RESULTS The title compounds were unambiguously characterized by infrared, 1 H NMR, 13 C NMR, and high-resolution mass spectroscopy. The results of the in vitro tests indicated that the majority of the title compounds showed potent inhibition of Arabidopsis thaliana HPPD ( At HPPD). Preliminary bioevaluation results revealed that a number of novel compounds displayed better or excellent herbicidal activity against broadleaf and monocotyledonous weeds. Compound III-5 showed herbicidal effects comparable to those of mesotrione at a rate of 150 g of active ingredient (ai)/ha for post-emergence application. The results of molecular dynamics verified that compound III-5 had a more stable protein-binding ability. Molecular docking results showed that compound III-5 and mesotrione shared homologous interplay with the surrounding residues. In addition, the enlarged aromatic ring system adds more force, and the hydrogen bond formed can enhance the synergy with π–π stacking. CONCLUSIONS The present work indicates that compound III-5 may be a potential lead structure for the development of new HPPD inhibitors.
研究领域:
植物保护
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农药化学
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计算生物学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2023
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IF 6.1
Li-Xia Zhao,Wei Hu,Zi-Bin Jiang,Jia-Yu Wang,Kui Wang,Shuang Gao,Ying Fu,Fei Ye
4-Hydroxyphenylpyruvate dioxygenase inhibitors (Echinochloa crus-galli 1.13.11.27, HPPD) have gained significant popularity as one of the best-selling herbicides worldwide. To identify highly effective HPPD inhibitors, a rational design approach utilizing bioisosterism was employed to create a series of 2-(arylformyl)cyclohexane-1,3-dione derivatives. A total of 29 novel compounds were synthesized and characterized through various techniques, including IR, 1H NMR, 13C NMR, and HRMS. Evaluation of their inhibitory activity against Arabidopsis thaliana HPPD (AtHPPD) revealed that certain derivatives exhibited superior potency compared to mesotrione (IC50 = 0.204 μM). Initial herbicidal activity tests demonstrated that compounds 27 and 28 were comparable to mesotrione in terms of weed control and crop safety, with compound 28 exhibiting enhanced safety in canola crops. Molecular docking analyses indicated that the quinoline rings of compounds 27 and 28 formed more stable π–π interactions with the amino acid residues Phe-360 and Phe-403 in the active cavity of AtHPPD, surpassing the benzene ring of mesotrione. Molecular dynamics simulations and molecular structure comparisons confirmed the robust binding capabilities of compounds 27 and 28 to AtHPPD. This study provides a valuable reference for the development of novel triketone herbicide structures, serving as a blueprint for future advancements in this field.
研究领域:
植物学
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药理学
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农业科学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Panpan Chen,Mengyuan Niu,Yang Qiu,Yuxin Zhang,Jing Xu,Rui Wang,Yi Wang
Understanding the physiological effects of herbicides on crops is crucial for crop production and environmental management. The effects of 4-hydroxyphenylpyruvate dioxygenase inhibitor (HPPDi) herbicides at different concentrations on chlorophyll content in maize leaves, fresh weight of roots, stems and leaves, and fluorescence substances and functional groups in root exudates (REs) were studied by UV-Vis absorption spectroscopy, fluorescence spectroscopy, Fourier transform infrared spectroscopy (FTIR) and two-dimensional correlation analysis (2D-COS). The results showed that 5 mg/L and 10 mg/L HPPDi herbicides inhibited the synthesis of chlorophyll in maize leaves. The weight of roots, stems and leaves of maize after application was lighter than that of the control group. HPPDi herbicides affected the early growth of maize seedlings, and the effect was most obvious at high concentration. Synchronous fluorescence spectrum and three-dimensional (3D) fluorescence spectrum revealed that the fluorescence intensity of protein, fulvic acid and humic acid in maize REs changed prominently. With the increase of HPPDi herbicides concentration, the fluorescence intensity decreased gradually. Through FTIR and 2D-COS, functional groups such as C-H, C O, Cl, NO 3 - , C-O and O-H were found to participate in the interaction between HPPDi herbicides and maize REs as binding sites. C-O, C-Cl and C-C have the strongest binding ability, while C C and C O of aromatic rings, quinones or ketones first take part in the binding between HPPDi herbicides and maize REs. The results can provide a theoretical basis for evaluating the safety of HPPDi herbicides on maize and a method for discovering the effects of pesticides on environmental media and plant physiological effects.
研究领域:
植物学
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环境科学
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农学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
·
IF 6.2
Enguang Nie,Dan Zhou,Dichen Ying,Zheng Lin,Jingyan Huang,Haiyan Wang,Zhen Yang
Few studies have examined the environmental fate of quinotrione, a new type of 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicide in plants. In this study, the uptake, translocation, and metabolism of quinotrione in pak choi were explored using 14C-labeling method and high-resolution mass spectrometry. The results showed that 57.7% of 14C-quinotrione was accumulated by pak choi via foliar application. The 14C-quinotrione concentration in the leaves (444.0 mg kg–1) at 5 d was 20 times higher than that in the roots (22.3 mg kg–1). The parent compound was the dominant residues (44.5–57.0%), while five metabolites were identified. Among these, hydroxylated quinotrione emerged as a key intermediate, with another three metabolites formed through hydrolysis, reduction, and oxidation. Notably, 6-(2,6-dioxocyclohexane-1-carbonyl)-1-methylquinazoline-2,4(1H,3H)-dione was the most abundant metabolite (17.7–22.2%). Our study provides further insight into the uptake and metabolism of HPPD herbicides in pak choi and the assessment of the environmental risk and food safety of quinotrione.
研究领域:
植物学
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环境化学
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农业化学
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农药科学
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DOI
PubMed
高影响因子
JOURNAL OF BIOSCIENCE AND BIOENGINEERING
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2022
·
IF 3.185
Qihao Zhang,Xiaohui Yang,Lin Lin,Shuhong Wu,Ping Wang,Wei Wei,Dongzhi Wei
Melanin has an increasing market demand in cosmetics, food, medicine as well as aerospace due to its unique properties. Heterologous expression of 4-hydroxyphenylpyruvate dioxygenase (HPPD) from the melanin-producing strain Streptomyces fungicidicus NW-EN1 in Escherichia coli shortened the fermentation cycle of melanin. HPPD catalyzed 4-hydrophenylpyruvate (HPP) to form homologous acid (HGA) and finally form melanin. The purified melanin had the highest absorption peak at 460 nm. Fourier transform infrared spectroscopy and scanning electron microscope scanning showed that the pigment had universal characteristic peaks. The presence of HGA, a predictor of pyomelanin, was identified by high-performance liquid chromatography analysis. The recombinant E. coli produced 804.4 ± 5.9 mg/L pyomelanin within 48 h. Metal ions had a great influence on the production of pyomelanin. Pyomelanin was stable in response to light intensity and had a protective effect against bacteria under UV irradiation. Meanwhile, we utilized the chromogenic effect after whole-cell catalysis to reflect the inhibition of the HPPD inhibitors (mesotrione and isoxaflutole) on HPPD by observing the color change. As a rapid method to test the action of inhibitors, this method is expected to be useful for the development of HPPD-inhibiting herbicides.
研究领域:
生物技术
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生物化学
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药学
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微生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2021
·
IF 5.279
Hao-Min Song,Li-Xia Zhao,Shuai-Qi Zhang,Tong Ye,Ying Fu,Fei Ye
Cinnamic acid, isolated from cinnamon bark, is a natural product with excellent bioactivity, and it effectively binds with cyclohexanedione to form novel 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors. According to the active sub-structure combination principle, a series of novel 3-hydroxy-2-cinnamoyl-2-en-1-one derivatives were designed and synthesized. The title compounds were characterized by infrared, 1H NMR, 13C NMR, and HRMS. The in vitro inhibitory activity of AtHPPD verified that compound II-13 showed the most activity with a half-maximal inhibitory concentration (IC50) value of 0.180 μM, which was superior to that of mesotrione (0.206 μM) in vitro. The preliminary herbicidal activity tests demonstrated that some compounds had good herbicidal activity especially compound II-13 at a concentration of 150 g ai/ha. The binding mode of AtHPPD through molecular docking indicated that two oxygens of compounds II-13 formed bidentate interactions with metal ions, and the benzene ring formed π-π accumulation effects with Phe-381 and Phe-424. The results of molecular dynamics simulations showed that compound II-13 exhibited a more stable binding ability with AtHPPD than mesotrione. This study provided insights into the development of natural and efficient herbicides in the future.
研究领域:
化学
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药理学
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农业科学
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分子生物学
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植物科学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Bo-Wen Ye,Li-Xia Zhao,Zi-Wei Wang,Juan Shi,Xin-Yu Leng,Shuang Gao,Ying Fu,Fei Ye
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.
研究领域:
农业化学
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植物科学
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药理学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）