Synthesis and Biological Activity Evaluation of Benzoxazinone-Pyrimidinedione Hybrids as Potent Protoporphyrinogen IX Oxidase Inhibitor

被引:18
作者
Zheng, Bai-Feng [1 ]
Zuo, Yang [1 ]
Huang, Guang-Yi [1 ]
Wang, Zhi-Zheng [1 ]
Ma, Jin-Yi [1 ]
Wu, Qiong-You [1 ]
Yang, Guang-Fu [1 ]
机构
[1] Cent China Normal Univ, Int Joint Res Ctr Intelligent Biosensor Technol &, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China
关键词
protoporphyrinogen IX oxidase; PPO inhibitor; benzoxazinone; pyrimidinedione; herbicide; VARIEGATE PORPHYRIA; HERBICIDAL ACTIVITY; DISCOVERY; DESIGN;
D O I
10.1021/acs.jafc.3c03593
中图分类号
S [农业科学];
学科分类号
09 ;
摘要
Protoporphyrinogen IX oxidase (PPO/Protox, E.C. 1.3.3.4) is recognized as one of the most important targets for herbicide discovery. In this study, we report our ongoing research efforts toward the discovery of novel PPO inhibitors. Specifically, we identified a highly potent new compound series containing a pyrimidinedione moiety and bearing a versatile building blockbenzoxazinone scaffold. Systematic bioassays resulted in the discovery of compound 7af, ethyl 4-(7-fluoro-6-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)-3- oxo-2,3- dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanoate, which exhibited broad-spectrum and excellent herbicidal activity at the dosage of 37.5 g a.i./ha through postemergence application. The inhibition constant (K-i) value of 7af to Nicotiana tabacum PPO (NtPPO) was 14 nM, while to human PPO (hPPO), it was 44.8 mu M, indicating a selective factor of 3200, making it the most selective PPO inhibitor to date. Moreover, molecular simulations further demonstrated the selectivity and the binding mechanism of 7af to NtPPO and hPPO. This study not only identifies a candidate that showed excellent in vivo bioactivity and high safety toward humans but also provides a paradigm for discovering PPO inhibitors with improved performance through molecular simulation and structure-guided optimization.
引用
收藏
页码:14221 / 14231
页数:11
相关论文
共 45 条
  • [1] Discovery, mode of action, resistance mechanisms, and plan of action for sustainable use of Group 14 herbicides
    Barker, Abigail L.
    Pawlak, John
    Duke, Stephen O.
    Beffa, Roland
    Tranel, Patrick J.
    Wuerffel, Joe
    Young, Bryan
    Porri, Aimone
    Liebl, Rex
    Aponte, Raphael
    Findley, Douglas
    Betz, Michael
    Lerchl, Jens
    Culpepper, Stanley
    Bradley, Kevin
    Dayan, Franck E.
    [J]. WEED SCIENCE, 2023, 71 (03) : 173 - 188
  • [2] ENZYMATIC DEFECT IN VARIEGATE PORPHYRIA - STUDIES WITH HUMAN CULTURED SKIN FIBROBLASTS
    BRENNER, DA
    BLOOMER, JR
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1980, 302 (14) : 765 - 769
  • [3] The function of PROTOPORPHYRINOGEN IX OXIDASE in chlorophyll biosynthesis requires oxidised plastoquinone in Chlamydomonas reinhardtii
    Brzezowski, Pawel
    Ksas, Brigitte
    Havaux, Michel
    Grimm, Bernhard
    Chazaux, Marie
    Peltier, Gilles
    Johnson, Xenie
    Alric, Jean
    [J]. COMMUNICATIONS BIOLOGY, 2019, 2 (1)
  • [4] Identification of an FAD superfamily containing protoporphyrinogen oxidases, monoamine oxidases, and phytoene desaturase -: Expression and characterization of phytoene desaturase of Myxococcus xanthus
    Dailey, TA
    Dailey, HA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (22) : 13658 - 13662
  • [5] Current Status and Future Prospects in Herbicide Discovery
    Dayan, Franck E.
    [J]. PLANTS-BASEL, 2019, 8 (09):
  • [6] Origins and structure of chloroplastic and mitochondrial plant protoporphyrinogen oxidases: implications for the evolution of herbicide resistance
    Dayan, Franck E.
    Barker, Abigail
    Tranel, Patrick J.
    [J]. PEST MANAGEMENT SCIENCE, 2018, 74 (10) : 2226 - 2234
  • [7] Design, Synthesis, and Structure-Activity Relationship of Novel Aryl-Substituted Formyl Oxazolidine Derivatives as Herbicide Safeners
    Ding, Yu
    Zhao, Dong-Mei
    Kang, Tao
    Shi, Juan
    Ye, Fei
    Fu, Ying
    [J]. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 2023, 71 (20) : 7654 - 7668
  • [8] The search for new herbicide mechanisms of action: Is there a 'holy grail'?
    Duke, Stephen O.
    Dayan, Franck E.
    [J]. PEST MANAGEMENT SCIENCE, 2022, 78 (04) : 1303 - 1313
  • [9] Analysis of a chemical plant defense mechanism in grasses
    Frey, M
    Chomet, P
    Glawischnig, E
    Stettner, C
    Grun, S
    Winklmair, A
    Eisenreich, W
    Bacher, A
    Meeley, RB
    Briggs, SP
    Simcox, K
    Gierl, A
    [J]. SCIENCE, 1997, 277 (5326) : 696 - 699
  • [10] Can new herbicide discovery allow weed management to outpace resistance evolution?
    Gaines, Todd A.
    Busi, Roberto
    Kuepper, Anita
    [J]. PEST MANAGEMENT SCIENCE, 2021, 77 (07) : 3036 - 3041