含双酰胺结构的氟吡菌酰胺衍生物的设计、合成及生物活性研究

doi:10.6023/cjoc202103021

摘要/Abstract

基于活性亚结构拼接法, 将双酰胺结构引入氟吡菌酰胺的骨架中, 设计并合成了22个含双酰胺结构的氟吡菌酰胺衍生物. 结构经过¹H NMR、¹³C NMR和HRMS鉴定, 目标化合物对4种植物病原真菌离体的抑制活性以及对秀丽隐杆线虫的离体杀虫活性也进行了研究. 结果显示, 在50 mg/L的浓度下, 大部分化合物对苹果腐烂病原菌及油菜菌核病原菌有较高的抑制活性, 抑制率在80%以上. 其中N-(2-(3-氯-5-(三氟甲基)吡啶-2-基)乙基)-2-(3-氟苯甲酰胺基)苯甲酰胺(7f)对苹果腐烂病原菌的EC₅₀为6.12 mg/L, 高于对照药剂氟吡菌酰胺(35.5 mg/L); 对苹果腐烂病原菌SDH酶抑制活性在100 μmol的浓度下达到90.1%; 对秀丽隐杆线虫的致死率在200 mg/L浓度下为87%. 分子对接结果表明, SDH可能是化合物的潜在靶标.

关键词: 琥珀酸脱氢酶, 杀线虫剂, 双酰胺, 氟吡菌酰胺

According to the principle of combination of bioactive substructure, the structure of diamide was introduced into fluopyram, and 22 novel fluopyram derivatives containing diamide were designed and synthesized. The structures of the target compounds were characterized by ¹H NMR, ¹³C NMR and HRMS. The inhibitory activities of the target compounds against four plant pathogenic fungi and in vitro insecticidal activities against Caenorhabditis elegans were studied. The results showed that under the concentration of 50 mg/L, most of the compounds showed moderate fungicide activity against Cytospora sp. and Sclerotinia sclerotiorum with inhibition rate over 80%. The EC₅₀ of N-(2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethyl)- 2-(3-fluorobenzamido)benzamide (7f) to Cytospora sp. was 6.12 mg/L, which is higher than fluopyram (35.5 mg/L), the SDH essay showed that enzyme inhibition rate of 7f reached 90.1%, and the mortality rate against C. elegans was 87% at 200 mg/L. The results of molecular docking show that the SDH may be a potential target of the compounds.

Key words: succinate dehydrogenase, nematicide, diamide, fluopyram

引用此文

许庆博, 梁培博, 路慧哲, 金淑惠, 董燕红, 张建军. 含双酰胺结构的氟吡菌酰胺衍生物的设计、合成及生物活性研究[J]. 有机化学, 2021, 41(8): 3116-3125.

Qingbo Xu, Peibo Liang, Huizhe Lu, Shuhui Jin, Yanhong Dong, Jianjun Zhang. Design, Synthesis and Bioactivity of Fluopyram Derivatives Containing Diamide Moiety[J]. Chinese Journal of Organic Chemistry, 2021, 41(8): 3116-3125.

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参考文献 25

[1]	Chen, L.; Zhao, B.; Fan, Z.; Hu, M.; Li, Q.; Hu, W.; Li, J.; Zhang, J. J. Agric. Food Chem. 2019, 67, 12357. doi: 10.1021/acs.jafc.9b03891
[2]	Silva, F. J.; Campos, V. P.; Oliveira, D. F.; Gomes, V. A.; Barros, A. F.; Din, Z. U.; Rodrigues‐Filho, E. J. Phytopathol. 2019, 167, 197.
[3]	Hu, Y.; Zhang, W.; Zhang, P.; Ruan, W.; Zhu, X. J. Agric. Food Chem. 2013, 61, 41. doi: 10.1021/jf304314g
[4]	Rao, S. V.; Sriram, K. I. J. Enzyme Inhib. Med. Chem. 1997, 11, 293.
[5]	Inaoka, D. K.; Shiba, T.; Sato, D.; Balogun, E. O.; Sasaki, T.; Nagahama, M.; Oda, M.; Matsuoka, S.; Ohmori, J.; Honma, T.; Inoue, M.; Kita, K.; Harada, S. Int. J. Mol. Sci. 2015, 16, 15287. doi: 10.3390/ijms160715287
[6]	Keohane, C. E.; Steele, A. D.; Fetzer, C.; Khowsathit, J.; Van Tyne, D.; Moynie, L.; Gilmore, M. S.; Karanicolas, J.; Sieber, S. A.; Wuest, W. M.. J. Am. Chem. Soc. 2018, 140, 1774. doi: 10.1021/jacs.7b11212
[7]	Diaz-Quiroz, D. C.; Cardona-Felix, C. S.; Viveros-Ceballos, J. L.; Reyes-Gonzalez, M. A.; Bolivar, F.; Ordonez, M.; Escalante, A. J. Enzyme Inhib. Med. Chem. 2018, 33, 397. doi: 10.1080/14756366.2017.1422125
[8]	Liang, P.; Shen, S.; Xu, Q.; Wang, S.; Jin, S.; Lu, H.; Dong, Y.; Zhang, Bioorg. Med. Chem. 2021, 29, 115846. doi: 10.1016/j.bmc.2020.115846
[9]	Li, A.; Li Z.; Zhao Y.; Yao T.; Cheng J.; Zhao J. Chin. J. Org. Chem. 2020, 40, 2836. (in Chinese) doi: 10.6023/cjoc202004013
	(李安邦, 李中珊, 赵洋, 姚停停, 程敬丽, 赵金浩, 有机化学, 2020, 40, 2836.) doi: 10.6023/cjoc202004013
[10]	Xiao, T.; Cheng, W.; Qian, W.; Zhang, T.; Lu, T.; Gao, Y.; Tang, X. Chin. J. Org. Chem. 2020, 40, 1704. (in Chinese) doi: 10.6023/cjoc201911034
	(肖婷婷, 程玮, 钱伟烽, 张婷婷, 陆童, 高扬, 唐孝荣, 有机化学, 2020, 40, 1704.) doi: 10.6023/cjoc201911034
[11]	Hua, X.; Liu, N.; Fan, Z.; Zong, G.; Ma, Y.; Lei, K.; Yin, H.; Wang, G. Chin. J. Org. Chem. 2019, 39, 2581. (in Chinese) doi: 10.6023/cjoc201903004
	(华学文, 刘南南, 范志金, 宗广宁, 马翼, 雷康, 殷昊, 王桂清, 有机化学, 2019, 39, 2581.) doi: 10.6023/cjoc201903004
[12]	Chen, J.; Yi, C.; Wang, S.; Wu, S.; Li, S.; Hu, D.; Song, B. Bioorg. Med. Chem. Lett. 2019, 29, 1203. doi: 10.1016/j.bmcl.2019.03.017
[13]	Good, J. A.; Silver, J.; Nunez-Otero, C.; Bahnan, W.; Krishnan, K. S.; Salin, O.; Engstrom, P.; Svensson, R.; Artursson, P.; Gylfe, A.; Bergstrom, S.; Almqvist, F. J. Med. Chem. 2016, 59, 2094. doi: 10.1021/acs.jmedchem.5b01759
[14]	Wang, P.-Y.; Shao, W.-B.; Xue, H.-T.; Fang, H.-S.; Zhou, J.; Wu, Z.-B.; Song, B.-A.; Yang, S. Res. Chem. Intermed. 2017, 43, 6115. doi: 10.1007/s11164-017-2980-x
[15]	Sharma, S.; Gangal, S.; Rauf, A.; Zahin, M. Arch. Pharm. (Weinheim, Ger.) 2008, 341, 714.
[16]	Nayyab, S.; O'Connor, M.; Brewster, J.; Gravier, J.; Jamieson, M.; Magno, E.; Miller, R. D.; Phelan, D.; Roohani, K.; Williard, P.; Basu, A.; Reid, C. W. ACS Infect. Dis. 2017, 3, 421. doi: 10.1021/acsinfecdis.7b00005 pmid: 28448118
[17]	Pejchalova, M.; Havelek, R.; Kralovec, K.; Ruzickova, Z.; Pejchal, V. Med. Chem. Res. 2017, 26, 1847. doi: 10.1007/s00044-017-1894-x
[18]	Clark, D. A.; Lahm, G. P.; Smith, B. K.; Barry, J. D.; Clagg, D. G. Bioorg. Med. Chem. 2008, 16, 3163. doi: 10.1016/j.bmc.2007.12.017
[19]	Moradi, W.; Himmler, W.; Muller, T.; Schnatterer, A.; Schlegel, G. EP 2014074212, 2015.
[20]	Chen, X.; Jia, H.; Li, Z.; Xu, X. Chin. Chem. Lett. 2019, 30, 1207. doi: 10.1016/j.cclet.2019.02.033
[21]	Wang, G.; Chen, X.; Deng, Y.; Li, Z.; Xu, X. J. Agric. Food Chem. 2015, 63, 6883. doi: 10.1021/acs.jafc.5b01762
[22]	Caboni, P.; Aissani, N.; Demurtas, M.; Ntalli, N.; Onnis, V. Pest Manage. Sci. 2016, 72, 125. doi: 10.1002/ps.3978
[23]	Tang, Z.; Li, X.; Yao, Y.; Qi, Y.; Wang, M.; Dai, N.; Wen, Y.; Wan, Y.; Peng, L. Bioorg. Med. Chem. 2019, 27, 2572. doi: 10.1016/j.bmc.2019.03.040
[24]	Zhang, A.; Yue, Y.; Yang, J.; Shi, J.; Tao, K.; Jin, H.; Hou, T. J. Agric. Food Chem. 2019, 67, 5008. doi: 10.1021/acs.jafc.9b00151
[25]	Zeun, R.; Scalliet, G.; Oostendorp, M. Pest Manage. Sci. 2013, 69, 527. doi: 10.1002/ps.2013.69.issue-4

Compd.	R	Mortality rate/%
7a	CF₃	20
7b	n-Propyl	45
7c	i-Propyl	45
7d	Ph	50
7e	2-FC₆H₄	55
7f	3-FC₆H₄	87
7g	4-FC₆H₄	70
7h	3-CH₃C₆H₄	60
7i	4-CH₃C₆H₄	0
7j	4-CH₃OC₆H₄	0
7k	2-BrC₆H₄	30
7l	4-BrC₆H₄	20
7m	2-CF₃C₆H₄	55
7n	3-CF₃C₆H₄	10
7o	4-NO₂C₆H₄	15
7p	3-ClC₆H₄	76
7q	4-ClC₆H₄	47
7r	4-PhC₆H₄	0
7s	2,4-Cl₂C₆H₄	81
7t	CH₂-(4-OCH₃)C₆H₄	70
7u	4-Cl-2-CF₃C₆H₄	50
7v	3,5-(NO₂)₂C₆H₄	66
Fluopyram		100

Compd.	R	Mortality rate/%
7a	CF₃	20
7b	n-Propyl	45
7c	i-Propyl	45
7d	Ph	50
7e	2-FC₆H₄	55
7f	3-FC₆H₄	87
7g	4-FC₆H₄	70
7h	3-CH₃C₆H₄	60
7i	4-CH₃C₆H₄	0
7j	4-CH₃OC₆H₄	0
7k	2-BrC₆H₄	30
7l	4-BrC₆H₄	20
7m	2-CF₃C₆H₄	55
7n	3-CF₃C₆H₄	10
7o	4-NO₂C₆H₄	15
7p	3-ClC₆H₄	76
7q	4-ClC₆H₄	47
7r	4-PhC₆H₄	0
7s	2,4-Cl₂C₆H₄	81
7t	CH₂-(4-OCH₃)C₆H₄	70
7u	4-Cl-2-CF₃C₆H₄	50
7v	3,5-(NO₂)₂C₆H₄	66
Fluopyram		100

Compd.	Inhibition rate (control effects)/%
Compd.	Cytospora sp.	Botryosphaeria berengeriana	Botrytis cinerea Pers	Sclerotinia sclerotiorum
7a	73.3	37.6	13.9	81.3
7b	73.3	16.1	36.1	72.9
7c	55.0	30.6	34.7	72.9
7d	89.4	55.9	41.7	88.2
7e	43.9	14.0	0	15.3
7f	92.5	53.8	55.6	88.9
7g	23.9	22.0	5.6	5.6
7h	84.4	2.7	4.9	69.4
7i	84.4	33.9	45.1	88.9
7j	79.4	32.8	55.6	90.3
7k	19.4	0	0	0
7l	62.2	10.8	10.0	85.4
7m	40.6	37.6	22.2	87.5
7n	84.4	2.7	4.9	69.4
7o	21.1	0	13.9	82.6
7p	65.0	0	54.5	32.5
7q	36.7	19.9	36.8	77.8
7r	22.8	8.1	0	12.5
7s	60.6	5.9	0	81.9
7t	61.1	34.9	0	14.6
7u	28.3	7.0	18.1	2.8
7v	34.4	15.1	0	80.6
Fluopyram	95.0	90.0	91.0	92.0

Compd.	Inhibition rate (control effects)/%
Compd.	Cytospora sp.	Botryosphaeria berengeriana	Botrytis cinerea Pers	Sclerotinia sclerotiorum
7a	73.3	37.6	13.9	81.3
7b	73.3	16.1	36.1	72.9
7c	55.0	30.6	34.7	72.9
7d	89.4	55.9	41.7	88.2
7e	43.9	14.0	0	15.3
7f	92.5	53.8	55.6	88.9
7g	23.9	22.0	5.6	5.6
7h	84.4	2.7	4.9	69.4
7i	84.4	33.9	45.1	88.9
7j	79.4	32.8	55.6	90.3
7k	19.4	0	0	0
7l	62.2	10.8	10.0	85.4
7m	40.6	37.6	22.2	87.5
7n	84.4	2.7	4.9	69.4
7o	21.1	0	13.9	82.6
7p	65.0	0	54.5	32.5
7q	36.7	19.9	36.8	77.8
7r	22.8	8.1	0	12.5
7s	60.6	5.9	0	81.9
7t	61.1	34.9	0	14.6
7u	28.3	7.0	18.1	2.8
7v	34.4	15.1	0	80.6
Fluopyram	95.0	90.0	91.0	92.0

Compd.	EC₅₀/(mol•L^–1)	Equation	R²
7d	7.39	Y=1.4509x+3.74	0.98
7f	6.12	Y=1.971x+3.3379	0.99
7i	16.4	Y=0.8564x+3.9593	0.99
Fluopyram	35.5	Y=1.8794x+2.0858	0.99