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2020 , Vol. 40 >Issue 11: 3953 - 3962

DOI: https://doi.org/10.6023/cjoc202003050

研究论文

烷氧基取代的嘧啶水杨酸衍生物的设计、合成及生物活性研究

  • 曲仁渝 ,
  • 蔡卓梅 ,
  • 杨景芳 ,
  • 刘玉超 ,
  • 陈琼 ,
  • 牛聪伟 ,
  • 席真 ,
  • 杨光富
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  • a 华中师范大学化学学院 农药与化学生物学教育部重点实验室智能生物传感技术与健康国际联合研究中心 武汉 430079;
    b 南开大学 元素有机化学国家重点实验室 天津 300071

收稿日期: 2020-03-20

  修回日期: 2020-04-12

  网络出版日期: 2020-04-23

基金资助

国家重点研发项目基金（No.2018YFD0200100）、国家自然科学基金（Nos.21837001，21772058，31901910）和中国博士后科学基金（No.2018M642880）资助项目.

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Design, Synthesis and Biological Activity of Pyrimidyl-Salicylate Derivatives Containing Alkoxy Moiety

  • Qu Renyu ,
  • Cai Zhuomei ,
  • Yang Jingfang ,
  • Liu Yuchao ,
  • Chen Qiong ,
  • Niu Congwei ,
  • Xi Zhen ,
  • Yang Guangfu
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  • a Key Laboratory of Pesticide&Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079;
    b State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071

Received date: 2020-03-20

  Revised date: 2020-04-12

  Online published: 2020-04-23

Supported by

Project supported by the National Key Research and Development Program (No. 2018YFD0200100), the National Natural Science Foundation of China (Nos. 21837001, 21772058, 31901910) and the China Postdoctoral Science Foundation (No. 2018M642880).

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摘要

为寻找新型乙酰羟酸合成酶（EC 2.2.1.6，AHAS）抑制剂以克服由靶标突变（P197L突变）所引起的杂草抗性问题，利用“构象柔性度分析”策略设计、合成了一系列烷氧基取代的嘧啶水杨酸衍生物.其中，9个化合物对P197L突变型AHAS的抗性倍数（RF值）均小于等于1，在酶水平上具有良好的反抗性.特别是2-（（4，6-二甲氧基嘧啶-2-基）氧基）-6-（2-氟乙氧基）苯甲酸（5l），被进一步确定为该系列最有效的反抗性AHAS抑制剂（RF＝0.31），不仅与氯磺隆（RF＝2060）和双草醚（RF＝4.57）相比抗性程度大幅降低，并且对野生型AtAHAS和P197L突变体的抑制活性均达到了亚微摩尔水平，优于双草醚.此外，在150 g ai/ha的施用剂量下，2-（（4，6-二甲氧基嘧啶-2-基）氧基）-6-（2-（甲氧基）乙氧基）苯甲酸（5a）、2-（（4，6-二甲氧基嘧啶-2-基）氧基）-6-（3-（甲氧基）丙氧基）苯甲酸（5f）、2-（（4，6-二甲氧基嘧啶-2-基）氧基）-6-（2-氟乙氧基）苯甲酸（5l）和2-（（4，6-二甲氧基嘧啶-2-基）氧基）-6-（2，2-二氟乙氧基）苯甲酸（5m）对敏感型和抗性（P197L-AHAS）播娘蒿同时表现出优异的除草活性.值得注意的是，即使在最低剂量37.5 g ai/ha下，化合物5l对这两种杂草的除草防效仍超过85%，表现出良好的活体反抗性，具有深入研究的价值.

关键词： 乙酰羟酸合成酶; P197L突变体; 反抗性; 构象柔性; 抗性杂草

本文引用格式

曲仁渝 , 蔡卓梅 , 杨景芳 , 刘玉超 , 陈琼 , 牛聪伟 , 席真 , 杨光富 . 烷氧基取代的嘧啶水杨酸衍生物的设计、合成及生物活性研究[J]. 有机化学, 2020 , 40(11) : 3953 -3962 . DOI: 10.6023/cjoc202003050

Abstract

In an attempt to search new antiresistance acetohydroxyacid synthase (AHAS, EC 2.2.1.6) inhibitors to combat weed resistance associated with AHAS mutation (P197L), a series of pyrimidyl-salicylate derivatives containing alkoxy side chain were designed via the strategy of “conformational flexibility analysis” and then synthesized. Nine compounds showed excellent antiresistance property against P197L mutant. Their resistance factor (RF) values ranged from 0.31 to 1.00. Especially, 2-((4,6-dimethoxypyrimidin-2-yl)oxy)-6-(2-fluoroethoxy)benzoic acid (5l) was further identified as the most promising antiresistance AHAS inhibitor due to quite low RF value (RF＝0.31) and sub-micromolar inhibition toward both wild-type AtAHAS and P197L mutant. Furthermore, 2-((4,6-dimethoxypyrimidin-2-yl)oxy)-6-(2-methoxyethoxy)benzoic acid (5a), 2-((4,6-dimethoxypyrimidin-2-yl)oxy)-6-(3-methoxypropoxy)benzoic acid (5f), 2-((4,6-dimethoxypyrimidin-2-yl)oxy)-6-(2-fluoroethoxy)benzoic acid (5l), and 2-(2,2-difluoroethoxy)-6-((4,6-dimethoxypyrimidin-2-yl)oxy)benzoic acid (5m) also exhibited potent herbicidal activities against sensitive and resistant (P197L-AHAS) Descurainia sophia at 150 g of active ingredient (ai)/ha. Even at the dosage as low as 37.5 g ai/ha, compound 5l still maintained over 85% weed control toward the above two weeds, which has the great potential to be developed as new lead to control herbicide-resistant weeds caused by P197L mutation.

Key words： acetohydroxyacid synthase; P197L mutant; antiresistance; conformation flexibility; resistant

参考文献

[1] Gianessi, L. P. Pest Manage. Sci. 2013, 47, 1099.
[2] (a) Ruegg, W. T.; Quadranti, M.; Zoschke, A. Weed Res. 2007, 47, 271.
(b) Renton, M.; Busi, R.; Neve, P.; Thornby, D.; Vila-Aiub, M. Pest Manage. Sci. 2014, 70, 1394.
[3] (a) Owen, M. D. Weed Sci. 2016, 70, 570.
(b) Green, J. M.; Owen, M. D. K. J. Agric. Food Chem. 2011, 59, 5819.
(c) Powles, S. B.; Yu, Q. Annu. Rev. Plant Biol. 2010, 61, 317.
[4] (a) Heap, I. Pest Manage. Sci. 2014, 70, 1306.
(b) Busi, R.; Vila-Aiub, M. M.; Beckie, H. J.; Gaines, T. A.; Goggin, D. E.; Kaundun, S. S.; Lacoste, M.; Neve, P.; Nissen, S. J.; Norsworthy, J. K.; Renton, M.; Shane, D. L.; Tranel, R. P. J.; Wright, T.; Yu, Q.; Powles, S. B. Evol. Appl. 2013, 6, 1218.
[5] Bar-Ilan, A.; Balan, V.; Tittmann, K.; Golbik, R.; Vyazmensky, M.; Huebner, G.; Barak, Z.; Chipman, D. M. Biochemistry 2001, 40, 11946.
[6] Qu, R. Y.; Liu, Y. C.; Chen, Q.; Yang G. F. J. Cent. China Norm. Univ. (Nat. Sci.) 2015, 49, 735(in Chinese) (曲仁渝, 刘玉超, 陈琼, 杨光富, 华中师范大学学报(自然科学版), 2015, 49, 735.)
[7] (a) Yu, Q.; Powles, S. B. Pest Manage. Sci. 2014, 70, 1340.
(b) Heap, I. The International Survey of Herbicide-Resistant Weeds, www.weedscience.org (accessed March 15, 2020).
[8] Corbett, C. A. L.; Tardif, F. J. Pest Manage. Sci. 2006, 62, 584.
[9] (a) Intanon, S.; Perez-Jones, A.; Hulting, A. G.; Mallory-Smith, C. A. Weed Sci. 2011, 59, 431.
(b) Délye, C.; Causse, R.; Michel, S. Pest Manage. Sci. 2016, 72, 89.
[10] (a) Ji, F. Q.; Niu, C. W.; Chen, C. N.; Chen, Q.; Yang, G. F.; Xi, Z.; Zhan, C. G. ChemMedChem 2008, 3, 1203.
(b) Liu, Y. C.; Qu, R. Y.; Chen, Q.; Yang, J. F.; Niu, C. W.; Xi, Z.; Yang, G. F. J. Agric. Food Chem. 2016, 64, 4845.
(c) Qu, R. Y.; Yang, J. F.; Liu, Y. C.; Chen, Q.; Hao, G. F.; Niu, C. W.; Xi, Z.; Yang, G. F. Pest Manage. Sci. 2017, 73, 1373.
(d) Qu, R. Y.; Yang, J. F.; Devendar, P.; Kang, W. M.; Liu, Y. C.; Chen, Q.; Niu, C. W.; Xi, Z.; Yang, G. F. J. Agric. Food Chem. 2017, 65, 11170.
(e) Qu, R. Y.; Yang, J. F.; Chen, Q.; Niu, C. W.; Xi, Z.; Yang, W. C.; Yang, G. F. Pest Manage. Sci. 2020, 76, 3403.
(f) Qu, R. Y.; Yan, Y. C.; Yang, J. F.; Chen, Q.; Yang, G. F. Chin. J. Org. Chem. 2019, 39, 2303(in Chinese) (曲仁渝, 严耀超, 杨景芳, 陈琼, 杨光富, 有机化学, 2019, 39, 2303.)
(g) Li, K. J.; Qu, R. Y.; Liu, Y. C.; Yang, J. F.; Devendar, P.; Chen, Q.; Niu, C. W.; Xi, Z.; Yang, G. F. J. Agric. Food Chem. 2018, 66, 3773.
[11] (a) Lin, H. Y.; Chen, X.; Chen, J. N.; Wang, D. W.; Wu, F. X.; Lin, S. Y.; Liu, J. J.; Dong, J. Q.; Zhan, C. G.; Wu, J. W.; Yang, W. C.; Yang, G. F. Research 2019, 2602414.
(b) Xiong, L.; Li, Hua.; Jiang, L. N.; Ge, J. M.; Yang, W. C.; Zhu, X. L.; Yang, G. F. J. Agric. Food Chem. 2017, 65, 1021.
(c) Xiong, L.; Zhu, X. L.; Gao, H. W.; Fu, Y.; Hu, S. Q.; Jiang, L. N.; Yang, W. C.; Yang, G. F. J. Agric. Food Chem. 2016, 64, 4830.
(d) Hao, G. F.; Wang, F.; Li, Hui, Zhu, X. L.; Yang, W. C.; Huang, L. S.; Wu, J. W.; Berry, E. A.; Yang, G. F. J. Am. Chem. Soc. 2012, 134, 11168.
[12] (a) Qu, R. Y.; Liu, Y. C.; Wu, Q. Y.; Chen, Q.; Yang, G. F. Tetrahedron 2015, 71, 8123.
(b) Hadfield, A.; Schweitzer, H.; Trova, M. P.; Green, K. Synth. Commun. 1994, 24, 1025.
[13] Garcia, M. D.; Nouwens, A.; Lonhienne, T. G.; Guddat, L. W. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 1091.
[14] Cui, H. L.; Zhang, C. X.; Wei, S. H.; Zhang, H. J.; Li, X. J.; Zhang, Y. Q.; Wang, G. Q. Weed Sci. 2011, 59, 376.
[15] (a) Souto, J. A.; Benedetti, R.; Otto, K.; Miceli, M.; Álvarez, R.; Altucci, L.; de Lera, A. R. ChemMedChem 2010, 5, 1530.
(b) Ghizzoni, M.; Boltjes, A.; Graaf, C. d.; Haisma, H. J.; Dekker, F. J. Bioorg. Med. Chem. 2010, 18, 5826.
[16] Liu, Y. C. Ph.D. Dissertation, Central China Normal University, Wuhan, 2014 (in Chinese) (刘玉超, 博士论文, 华中师范大学, 武汉, 2014.)
[17] Sitkoff, D.; Sharp, K. A.; Honig, B. J. Phys. Chem. 1994, 98, 1978.
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