Design, Synthesis and Bioactivity of Fluopyram Derivatives Containing Diamide Moiety

doi:10.6023/cjoc202103021

Abstract

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

Cite this article

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.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 8

References 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

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