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新型吡唑-喹唑啉二酮类对羟基苯丙酮酸双加氧酶抑制剂的设计、合成及生物活性

严耀超 王亚楠 何波 曲仁渝 南甲戌 林红艳 杨光富

严耀超, 王亚楠, 何波, 曲仁渝, 南甲戌, 林红艳, 杨光富. 新型吡唑-喹唑啉二酮类对羟基苯丙酮酸双加氧酶抑制剂的设计、合成及生物活性[J]. 农药学学报, 2022, 24(5): 1139-1151. doi: 10.16801/j.issn.1008-7303.2022.0089
引用本文: 严耀超, 王亚楠, 何波, 曲仁渝, 南甲戌, 林红艳, 杨光富. 新型吡唑-喹唑啉二酮类对羟基苯丙酮酸双加氧酶抑制剂的设计、合成及生物活性[J]. 农药学学报, 2022, 24(5): 1139-1151. doi: 10.16801/j.issn.1008-7303.2022.0089
YAN Yaochao, WANG Ya'nan, HE Bo, QU Renyu, NAN Jiaxu, LIN Hongyan, YANG Guangfu. Design, synthesis and biological activity of novel pyrazole-quinazoline-2,4-diones as 4-hydroxyphenylpyruvate dioxygenase inhibitors[J]. Chinese Journal of Pesticide Science, 2022, 24(5): 1139-1151. doi: 10.16801/j.issn.1008-7303.2022.0089
Citation: YAN Yaochao, WANG Ya'nan, HE Bo, QU Renyu, NAN Jiaxu, LIN Hongyan, YANG Guangfu. Design, synthesis and biological activity of novel pyrazole-quinazoline-2,4-diones as 4-hydroxyphenylpyruvate dioxygenase inhibitors[J]. Chinese Journal of Pesticide Science, 2022, 24(5): 1139-1151. doi: 10.16801/j.issn.1008-7303.2022.0089

新型吡唑-喹唑啉二酮类对羟基苯丙酮酸双加氧酶抑制剂的设计、合成及生物活性

doi: 10.16801/j.issn.1008-7303.2022.0089
基金项目: 国家自然科学基金项目 (31901910,21837001);国家重点研发计划 (2021YFD1700102).
详细信息

Design, synthesis and biological activity of novel pyrazole-quinazoline-2,4-diones as 4-hydroxyphenylpyruvate dioxygenase inhibitors

Funds: the National Natural Science Foundation of China (31901910, 21837001); the National Key R&D Program of China (2021YFD1700102).
  • 摘要: 对羟基苯丙酮酸双加氧酶 (HPPD) 抑制剂近年来因其高活性和低抗性风险成为了除草剂领域的研究热点。喹唑啉二酮被证明是一类具有潜力的骨架结构,为了继续发挥该骨架的优势,在前期工作的基础上,结合已有的构效关系研究结果,设计并合成了30个新型含喹唑啉二酮结构的吡唑类HPPD抑制剂,其结构均经过了高分辨质谱 (HRMS)、核磁共振氢谱 (1H NMR) 和碳谱 (13C NMR) 的表征。酶水平和活体活性测试结果表明,大部分目标化合物展现出了与对照药剂喹草酮相当甚至更优异的酶抑制活性。温室除草活性测试结果表明,目标化合物对6种供试杂草均有一定的生长抑制作用,特别是化合物 9-28 ,在有效成分150 g/hm2剂量下,对6种杂草的防治效果均在80%以上,其中对稗草和马唐的防治效果达100%。最后,培养了代表性化合物 9-28 与拟南芥HPPD的复合物晶体结构,从分子层面说明了该类抑制剂与靶标的结合模式,也为后续该类抑制剂的开发提供了一定的分子基础和设计思路。
  • 1  已上市的吡唑类HPPD抑制剂

    1.  Commercialized pyrazole-derived HPPD inhibitors

    2  目标化合物的设计思路

    2.  Design strategy of the target compounds

    3  目标化合物的合成路线

    3.  Synthetic route of the target compounds

    图  1  目标化合物9-28与AtHPPD的复合物晶体结构

    A. 化合物9-28AtHPPD的结合模式;B. 化合物9-28的电子云密度轮廓图;C. 化合物9-28与活性腔腔口处氨基酸残基的相互作用图;D. AtHPPD-9-28AtHPPD-喹草酮的叠合图。

    Figure  1.  Co-crystal structure of AtHPPD-9-28

    A. Binding mode of compound 9-28 with AtHPPD; B. 2Fo-Fc map (contoured at 1.0 σ) of compound 9-28; C. Interaction between compound 9-28 and the residues around the entrance of the active pocket; D. Superposition of the binding modes of compound 9-28 and benquitrione in AtHPPD.

    表  1  目标化合物9-1~9-30的温室除草活性 (150 g/hm2) 和对AtHPPD的IC50

    Table  1.   Greenhouse herbicidal activities of compounds 9-1-9-30 at 150 g/hm2 and IC50 values against AtHPPD

    化合物
    Compd.
    R抑制率b
    Inhibition rateb/%
    AtHPPD 抑制活性
    AtHPPD inhibitory activity
    稗草
    E. c.a
    狗尾草
    S. v.
    马唐
    D. s.
    苋菜
    A. r.

    C. s.
    苘麻
    A. t.
    IC50/(μmol/L)
    9-1 -CH3 B C C D B B 0.295 ± 0.002
    9-2 -CH2CH3 C A C A B C 0.227 ± 0.022
    9-3 -CH2CH2CH3 B B B C C B 0.208 ± 0.010
    9-4 -CH2CH2CH2CH3 D E D D E E 0.311 ± 0.009
    9-5 -CH(CH3)2 C C C B B A 0.183 ± 0.009
    9-6 -CH(CH3)CH2CH3 D B E B B B 0.172 ± 0.014
    9-7 -CH2CH2F C A B D D E 0.254 ± 0.018
    9-8 -CH2CHF2 B B B D D D 0.274 ± 0.018
    9-9 -CH2CF3 C B B D D E 0.336 ± 0.033
    9-10 -CH2CH2CH2F B A B C D B 0.228 ± 0.007
    9-11 -CH2CH2CF3 B B B D E E 0.294 ± 0.014
    9-12 -CH2CH2OCH3 C D D D D A 0.253 ± 0.017
    9-13 -CH2CH=CH2 B B E B A B 0.176 ± 0.001
    9-14 -CH2C≡CH A B C B B A 0.190 ± 0.002
    9-15 -CH2CH=C(CH3)2 D E F E A F 0.182 ± 0.016
    9-16 E B D C E E 0.463 ± 0.015
    9-17 B B E C D D 0.238 ± 0.005
    9-18 B B B A D B 0.157 ± 0.008
    9-19 A B B B A C 0.169 ± 0.002
    9-20 D C E C E E 0.172 ± 0.011
    9-21 C D E D D D 0.208 ± 0.010
    9-22 E E C D D D 0.332 ± 0.010
    9-23 D D E D A E 0.211 ± 0.002
    9-24 E F E D E E 0.136 ± 0.003
    9-25 F F F F F F 0.155 ± 0.008
    9-26 E D E D D D 0.160 ± 0.012
    9-27 D E D F D D 0.183 ± 0.017
    9-28 A B A B B B 0.370 ± 0.026
    9-29 B B D A A C 0.199 ± 0.010
    9-30 B B B A A C 0.247 ± 0.013
    喹草酮 B B B B A B 0.375 ± 0.012
    注(Note):a Echinochloa crus-galli (E. c.), Setaria viridis (S. v.), Digitaria sanguinalis (D. s.), Amaranthus retroflexus (A. r.), Chenopodium serotinum (C. s.), and Abutilon theophrasti (A. t.). b A = 100%; B ≥ 80%; C ≥ 60%; D ≥ 40%; E ≥ 20%; F < 20%.
    下载: 导出CSV
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出版历程
  • 收稿日期:  2022-07-08
  • 录用日期:  2022-08-20
  • 网络出版日期:  2022-08-24
  • 刊出日期:  2022-10-10

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