• 百种中国杰出学术期刊
  • 中国精品科技期刊
  • 中国高校百佳科技期刊
  • 中国高校精品科技期刊
  • 中国国际影响力优秀学术期刊
  • 中国科技核心期刊

留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

杀菌剂氟苯醚酰胺的创制

曾令强 罗睿童 陈琼 郝格非 朱晓磊 杨光富

曾令强, 罗睿童, 陈琼, 郝格非, 朱晓磊, 杨光富. 杀菌剂氟苯醚酰胺的创制[J]. 农药学学报, 2022, 24(5): 895-903. doi: 10.16801/j.issn.1008-7303.2022.0028
引用本文: 曾令强, 罗睿童, 陈琼, 郝格非, 朱晓磊, 杨光富. 杀菌剂氟苯醚酰胺的创制[J]. 农药学学报, 2022, 24(5): 895-903. doi: 10.16801/j.issn.1008-7303.2022.0028
ZENG Lingqiang, LUO Ruitong, CHEN Qiong, HAO Gefei, ZHU Xiaolei, YANG Guangfu. Discovery of fungicide flubeneteram[J]. Chinese Journal of Pesticide Science, 2022, 24(5): 895-903. doi: 10.16801/j.issn.1008-7303.2022.0028
Citation: ZENG Lingqiang, LUO Ruitong, CHEN Qiong, HAO Gefei, ZHU Xiaolei, YANG Guangfu. Discovery of fungicide flubeneteram[J]. Chinese Journal of Pesticide Science, 2022, 24(5): 895-903. doi: 10.16801/j.issn.1008-7303.2022.0028

杀菌剂氟苯醚酰胺的创制

doi: 10.16801/j.issn.1008-7303.2022.0028
基金项目: 湖北省科技厅重点研发项目 (2020BBA052) ;国家自然科学基金面上项目 (21977035,21837001).
详细信息

Discovery of fungicide flubeneteram

Funds: the Key Research and Development Program of Hubei Province (2020BBA052); the National Natural Science Foundation of China (21977035, 21837001).
  • 摘要: 琥珀酸脱氢酶 (succinate dehydrogenase, SDH) 是重要的杀菌剂靶标之一,而很多植物病原菌对靶向SDH的杀菌剂已经产生了较为严重的抗药性,因此新型靶向SDH的杀菌剂设计显得尤为重要。基于药效团连接碎片的虚拟筛选 (PFVS) 是一种独立于生物物理技术的高通量药物发现方法,采用PFVS方法成功获得了靶向SDH的新型杀菌剂候选化合物—氟苯醚酰胺。本文主要从PFVS原理、先导化合物的发现、取代基的修饰以及杀菌活性研究等方面对氟苯醚酰胺的创制进行系统分析。氟苯醚酰胺创制的案例分析可为农药研究工作者提供新思路和新方法。
  • 1  氟苯醚酰胺 (试验代号:Y13149,本文中化合物11) 的化学结构式

    1.  The chemical structure of flubeneteram (also named Y13149, compound 11)

    图  1  药效团连接碎片虚拟筛选工作流程[23]

    Figure  1.  Work flow of PFVS[23]

    2  10个商品化SDHI的化学结构式(红色表示酸部分,蓝色表示胺部分)[24]

    2.  The chemical structures of ten commercial SDHI (The acid and the amine parts were colored by red and blue, respectively)[24]

    图  2  10个商品化SDHI与SDH作用方式叠合显示图 (sub_amine为胺部分,sub_acid为酸部分,HEM为血红素)[24]

    Figure  2.  The overlay of the binding model of ten SDHI with SDH (sub_amine means the amine part, sub_acid means the acid part and HEM stands for heme)[24]

    3  基于PFVS筛选得到的8个hit化合物 (蓝色表示PFVS确定的部分)[25]

    3.  Chemical structures of eight hit compounds identified by PFVS (The fragments determined by PFVS are shown in blue)[25]

    图  3  结合模式显示图

    注:(A) hit 4 (黄色棍状显示)与猪心SDH的结合方式; (B) 氟苯醚酰胺 (黄色棍状显示)与猪心SDH的结合方式; (C) 氟酰胺衍生物 (黄色棍状显示) 与猪心SDH结合方式 (PDB ID:3ABV); (D) 氟苯醚酰胺 (橙色棍状显示)与水稻纹枯病菌SDH的结合方式; (E) 氟苯醚酰胺与猪心SDH (玫红色和黄色棍状显示) 和水稻纹枯病菌SDH (灰色和绿色棍状显示) 结合方式显示叠合图; (F) 噻呋酰胺与猪心SDH (玫红色和黄色棍状显示) 和水稻纹枯病菌SDH (灰色和绿色棍状显示) 结合方式显示叠合图;为了便于展示,C_M39/W的含义为猪心中SDH为C_M39,而水稻纹枯病中SDH为C_W39;以此类推,C_W35/P表示的是猪心中SDH为C_W35,而水稻纹枯病中SDH为C_P35;C_I30/F表示的是猪心中SDH为C_I30,而水稻纹枯病中SDH为C_F30 [26]

    Figure  3.  The binding modes

    Note: (A) hit 4 (yellow stick) with porcine SDH. (B) flubeneteram (yellow stick) with porcine SDH. (C) flutolanil derivatives (yellow stick) with porcine SDH in crystal structure 3ABV. (D) flubeneteram (orange stick) with Rhizoctonia solani (R. solani) SDH. (E) Overlay of flubeneteram binding with porcine SDH (represented by magenta and yellow stick) and R. solani SDH (represented by gray and green stick). (F) Overlay of thifluzamide binding with porcine SDH (represented by magenta and yellow) and R. solani SDH (represented by gray and green sticks). C_M39/W, C_W35/P, and C_I30/F respectively indicate C_M39, C_W35, and C_I30 in porcine SDH and C_W39, C_P35, and C_F30 in R. solani SDH. For clarity, just some key residues are shown[26]

    图  4  化合物设计思路

    注:a指200 mg/L下该化合物对水稻纹枯病的防治效果; b指200 mg/L下该化合物对黄瓜白粉病的防治效果。

    Figure  4.  Compound design strategy

    Note: a The control efficacy of compound against rice sheath blight at a concentration of 200 mg/L . b The control efficacy of compound against cucumber powdery mildew at a concentration of 200 mg/L.

    图  5  氟苯醚酰胺的作用谱

    注:图中0~5数字代表杀菌活性,5:很优秀;4:较好;一般认为4以上具有商业价值,3以上具有应用价值。

    Figure  5.  The antifungal spectrum of flubeneteram

    Note: The number of 0-5 represents the activity of compound against the fungal. 5 indicates that the activity is very excellent against the fungal, 4 indicates that the activity is good. And in general, the compound with more than 4 has commercial value, and more than 3 has application value.

    4  化合物11合成路线[26]

    4.  Synthetic route of compound 11[26]

    表  1  10个商品化SDHI与SDH的结合自由能 (kcal/mol)c[24]

    Table  1.   The binding free energies of ten SDHI with the Q-site of SDH (kcal/mol)c[24]


    化合物
    Compound

    Eele

    Evdw

    Gnp

    Gpol

    H

    TS

    Gcal

    Gexpa

    Kib/(μmol/L)
    噻呋酰胺 thifluzamide −10.62 −43.99 −4.76 31.02 −28.35 11.21 −17.14 −9.10 0.20
    吡噻菌胺 penthiopyrad −13.84 −41.91 −5.10 34.28 −26.57 13.54 −13.03 −7.35 3.90
    萎锈灵 carboxin −14.42 −35.65 −4.15 29.48 −24.74 12.16 −12.58 −7.25 4.59
    啶酰菌胺 boscalid −18.50 −39.68 −4.66 39.76 −23.08 11.02 −12.06 −6.84 9.20
    麦锈灵 benodanil −10.38 −34.43 −4.20 27.87 −21.14 10.13 −11.01 −6.63 13.17
    氟酰胺 flutolanil −9.75 −38.41 −4.68 32.28 −20.57 9.76 −10.81 −6.17 28.88
    呋吡菌胺 furamepyr −13.94 −37.16 −4.58 34.69 −20.99 10.43 −10.56 −6.16 29.27
    灭锈胺 mepronil −11.92 −36.64 −4.57 32.97 −20.16 9.59 −10.57 −6.11 31.81
    氧化萎锈灵 oxycarboxin −20.09 −38.22 −4.26 41.65 −20.93 10.48 −10.45 −5.56 81.02
    甲呋酰胺 fenfuram −15.03 −32.00 −3.90 29.13 −21.79 11.64 −10.15 −5.39 108.40
    注:aGexp = −RTlnKib使用琥珀酸-DCIP体系测定。c 1 kcal/mol = 4.184 kJ/mol。Note:aGexp = −RTlnKi; bDetermined with the succinate-DCIP system. c1 kcal/mol = 4.184 kJ/mol.
    下载: 导出CSV

    表  2  化合物对猪心SDH的IC50[26]

    Table  2.   IC50 value of compound against porcine SDH[26]

    化合物
    Compound
    R1R2IC50 值 (猪心 SDH)
    IC50 value (porcine SDH)/(μmol/L)
    化合物
    Compound
    R1R2IC50 值 (猪心 SDH)
    IC50 value (porcine SDH)/(μmol/L)
    hit 4 CF3 H 19.79 7 CF3 2,4-Cl2 2.70
    2 CF3 2-Cl 1.98 8 CF3 2-Cl-4-CF3 0.28
    3 CF3 3-Cl 36.9 9 CHF2 2-Cl 1.13
    4 CF3 4-F >100 10 CHF2 2,4-Cl2 0.40
    5 CF3 4-Cl 4.90 11 CHF2 2-Cl-4-CF3 0.11
    6 CF3 4-CN >100 吡噻菌胺 penthiopyrad 1.29
    下载: 导出CSV

    表  3  化合物9~11活体杀菌活性[26]

    Table  3.   Fungicidal activities of compounds 9-11 in vivo[26]

    化合物
    Compound
    质量浓度
    Concentration/
    (mg/L)
    防治效果
    Control efficacy/%
    化合物
    Compound
    质量浓度
    Concentration/
    (mg/L)
    防治效果
    Control efficacy/%
    水稻纹枯病
    Rice sheath
    blight
    黄瓜白粉病
    Cucumber powdery
    mildew
    水稻纹枯病
    Rice sheath
    blight
    黄瓜白粉病
    Cucumber powdery
    mildew
    9 100 100 100 11 100 100 100
    50 100 83 50 100 100
    25 80 41 25 99 94
    12.5 72 7 12.5 95 67
    6.25 75 0 6.25 70 0
    10 100 100 噻呋酰胺
    thifluzamide
    100 100 100
    50 98 50 100 63
    25 95 25 82 22
    12.5 82 12.5 61 0
    6.25 69 6.25 54 0
    注:— 表示未测定。Note: — Indicates untested.
    下载: 导出CSV

    表  4  化合物11对水稻纹枯病的田间药效试验[26,28]

    Table  4.   Control efficacy of compound 11 against R. solani in field trials [26,28]

    药剂处理
    Treatment
    有效成分用量
    Amount of active ingredient/(g/hm2)
    第 2 次施药后 7 d
    7 days after the second spraying
    第 2 次施药后 21 d
    21 days after the second spraying
    病情指数
    Disease
    index
    防治效果
    Control
    efficacy/%
    病情指数
    Disease
    index
    防治效果
    Control
    efficacy/%
    浙江宁波
    Ningbo, Zhejiang
    11
    (5%, EC)
    112.5 1.59 77.2 0.99 88.5
    75.0 2.12 69.6 1.62 81.2
    37.5 2.40 65.5 1.87 78.3
    噻呋酰胺
    thifluzamide (24%, SC)
    75.0 3.59 48.4 2.12 75.4
    清水 Water 0 6.97 0 8.63 0
    浙江绍兴
    Shaoxing, Zhejiang
    11
    (5%, EC)
    112.5 2.22 83.4 6.70 83.6
    75.0 2.78 78.8 9.00 78.0
    37.5 3.70 72.9 11.9 70.6
    噻呋酰胺
    thifluzamide (24%, SC)
    75.0 2.63 80.8 8.52 79.1
    清水 Water 0 6.97 0.00 8.63 0.00
    下载: 导出CSV
  • [1] HAGERHALL C. Succinate: quinone oxidoreductases. Variations on a conserved theme[J]. Biochim Biophys Acta, 1997, 1320(2): 107-141. doi: 10.1016/S0005-2728(97)00019-4
    [2] MELIN F, HELLWIG P. Redox properties of the membrane proteins from the respiratory chain[J]. Chem Rev, 2020, 120(18): 10244-10297. doi: 10.1021/acs.chemrev.0c00249
    [3] LANCASTER C R, KROGER A, AUER M, et al. Structure of fumarate reductase from Wolinella succinogenes at 2.2 Å resolution[J]. Nature, 1999, 402(6760): 377-385. doi: 10.1038/46483
    [4] LANCASTER C R D. Succinate: quinone oxidoreductases: an overview[J]. Biochim Biophys Acta, 2002, 1553(1-2): 1-6. doi: 10.1016/S0005-2728(01)00240-7
    [5] CECCHINI G. Function and structure of complex II of the respiratory chain[J]. Annu Rev Biochem, 2003, 72: 77-109. doi: 10.1146/annurev.biochem.72.121801.161700
    [6] LI S Q, LI X S, ZHANG H M, et al. The research progress in and perspective of potential fungicides: succinate dehydrogenase inhibitors[J]. Bioorg Med Chem, 2021, 50: 116476. doi: 10.1016/j.bmc.2021.116476
    [7] Fungal control agents by cross resistance pattern and mode of action 2021[EB/OL]. (2021). https://www.frac.info/docs/default-source/publications/frac-mode-of-action-poster/frac-moa-poster-2021.pdf?sfvrsn=a6f6499a_2.
    [8] 胡伟群. 病原真菌对琥珀酸脱氢酶抑制剂抗性研究进展[J]. 世界农药, 2020, 42(12): 1-5.

    HU W Q. Research progresses in resistance of plant pathogenic fungi to succinate dehydrogenase inhibitors[J]. World Pestic, 2020, 42(12): 1-5.
    [9] VIELBA-FERNÁNDEZ A, POLONIO Á, RUIZ-JIMÉNEZ L, et al. Fungicide resistance in powdery mildew fungi[J]. Microorganisms, 2020, 8(9): 1431. doi: 10.3390/microorganisms8091431
    [10] ZHU F D, SHI Y X, XIE X W, et al. Occurrence, distribution, and characteristics of boscalid-resistant Corynespora cassiicola in China[J]. Plant Dis, 2019, 103(1): 69-76. doi: 10.1094/PDIS-11-17-1760-RE
    [11] OUTWATER C A, PROFFER T J, ROTHWELL N L, et al. Boscalid resistance in Blumeriella jaapii: distribution, effect on field efficacy, and molecular characterization[J]. Plant Dis, 2019, 103(6): 1112-1118. doi: 10.1094/PDIS-09-18-1555-RE
    [12] CHERRAD S, CHARNAY A, HERNANDEZ C, et al. Emergence of boscalid-resistant strains of Erysiphe necator in French vineyards[J]. Microbiol Res, 2018, 216: 79-84. doi: 10.1016/j.micres.2018.08.007
    [13] SAMARAS A, HADJIPETROU C, KARAOGLANIDIS G. Bacillus amyloliquefaciens strain QST713 may contribute to the management of SDHI resistance in Botrytis cinerea[J]. Pest Manag Sci, 2021, 77(3): 1316-1327. doi: 10.1002/ps.6145
    [14] MELLO F E, MATHIONI S M, FANTIN L H, et al. Sensitivity assessment and SDHC-I86F mutation frequency of Phakopsora pachyrhizi populations to benzovindiflupyr and fluxapyroxad fungicides from 2015 to 2019 in Brazil[J]. Pest Manag Sci, 2021, 77(10): 4331-4339. doi: 10.1002/ps.6466
    [15] LIU S M, FU L Y, TAN H H, et al. Resistance to boscalid in Botrytis cinerea from greenhouse-grown tomato[J]. Plant Dis, 2021, 105(3): 628-635. doi: 10.1094/PDIS-06-20-1191-RE
    [16] IMRAN M, ALI E F, HASSAN S, et al. Characterization and sensitivity of Botrytis cinerea to benzimidazole and succinate dehydrogenase inhibitors fungicides, and illustration of the resistance profile[J]. Australas Plant Pathol, 2021, 50(5): 589-601. doi: 10.1007/s13313-021-00803-2
    [17] SANG H, LEE H B. Molecular mechanisms of succinate dehydrogenase inhibitor resistance in phytopathogenic fungi[J]. Res Plant Dis, 2020, 26(1): 1-7. doi: 10.5423/RPD.2020.26.1.1
    [18] MIYAMOTO T, HAYASHI K, OKADA R, et al. Resistance to succinate dehydrogenase inhibitors in field isolates of Podosphaera xanthii on cucumber: monitoring, cross-resistance patterns and molecular characterization[J]. Pestic Biochem Physiol, 2020, 169: 104646. doi: 10.1016/j.pestbp.2020.104646
    [19] SIEROTZKI H, SCALLIET G. A review of current knowledge of resistance aspects for the next-generation succinate dehydrogenase inhibitor fungicides[J]. Phytopathology, 2013, 103(9): 880-887. doi: 10.1094/PHYTO-01-13-0009-RVW
    [20] AVENOT H F, MICHAILIDES T J. Progress in understanding molecular mechanisms and evolution of resistance to succinate dehydrogenase inhibiting (SDHI) fungicides in phytopathogenic fungi[J]. Crop Prot, 2010, 29(7): 643-651. doi: 10.1016/j.cropro.2010.02.019
    [21] 刘承先. 3, 4, 5-三氟-2′-硝基联苯的工艺合成[J]. 化工进展, 2015, 34(4): 1122-1125.

    LIU C X. Synthesis of 3,4,5-trifluoro-2′-nitro-1,1′-biphenyl[J]. Chem Ind Eng Prog, 2015, 34(4): 1122-1125.
    [22] 张一宾. 琥珀酸脱氢酶抑制剂类杀菌剂isofetamid的开发[J]. 世界农药, 2014, 36(3): 30-32. doi: 10.3969/j.issn.1009-6485.2014.03.007

    ZHANG Y B. Research and development of a SDHI fungicide: isofetamid[J]. World Pestic, 2014, 36(3): 30-32. doi: 10.3969/j.issn.1009-6485.2014.03.007
    [23] HAO G F, WANG F, LI H, et al. Computational discovery of picomolar Qo site inhibitors of cytochrome bc1 complex[J]. J Am Chem Soc, 2012, 134(27): 11168-11176. doi: 10.1021/ja3001908
    [24] ZHU X L, XIONG L, LI H, et al. Computational and experimental insight into the molecular mechanism of carboxamide inhibitors of succinate-ubquinone oxidoreductase[J]. ChemMedChem, 2014, 9(7): 1512-1521. doi: 10.1002/cmdc.201300456
    [25] XIONG L, ZHU X L, GAO H W, et al. Discovery of potent succinate-ubiquinone oxidoreductase inhibitors via pharmacophore-linked fragment virtual screening approach[J]. J Agric Food Chem, 2016, 64(24): 4830-4837. doi: 10.1021/acs.jafc.6b00325
    [26] XIONG L, LI H, JIANG L N, et al. Structure-based discovery of potential fungicides as succinate ubiquinone oxidoreductase inhibitors[J] J Agric Food Chem, 2017, 65(5): 1021-1029.
    [27] XIONG L, ZHU X L, SHEN Y Q, et al. Discovery of N-benzoxazol-5-yl-pyrazole-4-carboxamides as nanomolar SQR inhibitors[J]. Eur J Med Chem, 2015, 95: 424-434. doi: 10.1016/j.ejmech.2015.03.060
    [28] 熊力. 新型琥珀酸脱氢酶抑制剂的设计、合成及生物活性研究 [D]. 武汉: 华中师范大学, 2016.

    XIONG L. Design, synthesis and biological activities of novel SDH inhibitors[D]. Wuhan: Central China Normal University, 2016.
  • 加载中
图(9) / 表(4)
计量
  • 文章访问数:  408
  • HTML全文浏览量:  122
  • PDF下载量:  128
  • 被引次数: 0
出版历程
  • 收稿日期:  2021-11-08
  • 录用日期:  2022-01-05
  • 网络出版日期:  2022-03-24
  • 刊出日期:  2022-10-10

目录

    /

    返回文章
    返回