Screening and Optimization of Novel Low Bee-Toxicity Phenylace- tohydrazone Compounds Based on Insect nAChR Selectivity

doi:10.6023/cjoc202101028

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (7): 2774-2787.DOI: 10.6023/cjoc202101028 Previous Articles Next Articles

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基于昆虫nAChR选择性的新型低蜂毒苯乙酰腙类似物的筛选和优化

杨朝凯^a, 武霞^a, 张晋陆^a, 路星星^a, 李想^a, 蒋志洋^a, 宋敦伦^b, 段红霞^a^,^*(), 杨新玲^a

a 中国农业大学理学院应用化学系农药研究创新中心北京 100193
b 中国农业大学植物保护学院昆虫系北京 100193

收稿日期:2021-01-18 修回日期:2021-03-16 发布日期:2021-04-12
通讯作者: 段红霞
基金资助:
国家自然科学基金(31972289); 国家自然科学基金(31772207); 国家自然科学基金(30800719); 国家重点研发计划(2017YFD0200504); 植物病虫害生物学国家重点实验室(SKLOF201902)

Screening and Optimization of Novel Low Bee-Toxicity Phenylace- tohydrazone Compounds Based on Insect nAChR Selectivity

Zhaokai Yang^a, Xia Wu^a, Jinlu Zhang^a, Xingxing Lu^a, Xiang Li^a, Zhiyang Jiang^a, Dunlun Song^b, Hongxia Duan^a(), Xinling Yang^a

a Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193
b b Department of Entomology, College of Plant Protection, China Agricultural University, Beijing 100193

Received:2021-01-18 Revised:2021-03-16 Published:2021-04-12
Contact: Hongxia Duan
Supported by:
National Natural Science Foundation(31972289); National Natural Science Foundation(31772207); National Natural Science Foundation(30800719); National Key Research and Development Plan(2017YFD0200504); State Key Laboratory for Biology of Plant Diseases and Insect Pests(SKLOF201902)

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Abstract

Increasing numbers of neonicotinoids have recently been banned by the European Union (EU) and the United States of America (USA) due to their potential high risk to pollinating bees. In this work, a phenylacetohydrazone compound VS-04 was found via scaffold hopping to exert good mortality rate against soybean aphids based on a double combinational strategy of virtual screening and bioassay technique. The molecular interaction mode to honeybee nicotinic acetylcholine receptor (nAChR) for the newly found compound VS-04obviously differed from that of the known imidacloprid. The newly synthesized phenylacetohydrazone compounds 3c and 3e caused soybean aphids to have a moderate mortality rate of approximately 70% at a concentration of 500 μg/mL. Importantly, the bee-toxicity study confirmed that compounds 3c and 3e showed much lower acute contact toxicity with LD₅₀ value (30.35 and 124.4 μg/bee) of 3~4 orders of magnitude than that of imidacloprid (0.019 μg/bee). The hydrazone substructure of compound 3c was found to be aL-shape low-energy conformation confirmed by a crystal structure of its analog 3m and inversely point towardα subunit of honeybee receptor via a molecular interaction study, indicating its potential low bee-toxicity. Compounds 4fand 4g (optimized derivatives of 3e) indeed showed better insecticidal activity against soybean aphids with moderate LC₅₀ values of 83.42 and 66.44 μg/mL, respectively, compared with 3e (147.30 μg/mL). This work facilitates the discovery of suitable and ecofriendly candidates as alternatives to neonicotinoids based on different insect nAChR structure.

Key words: neonicotinoid, Aplysia californiaacetylcholine binding protein (Ac-AChBP), scaffold hopping, phenylacetohydrazone compounds, target and nontarget selectivity

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Zhaokai Yang, Xia Wu, Jinlu Zhang, Xingxing Lu, Xiang Li, Zhiyang Jiang, Dunlun Song, Hongxia Duan, Xinling Yang. Screening and Optimization of Novel Low Bee-Toxicity Phenylace- tohydrazone Compounds Based on Insect nAChR Selectivity[J]. Chinese Journal of Organic Chemistry, 2021, 41(7): 2774-2787.

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Fig. & Tab. 13

Figure 1. Structure of lead VS-04 separated into three parts: benzene ring A, acylhydrazone chain B, and aromatic ring C (a), and docking modes of VS-04 and imidacloprid in the model of a functional subunit hybrid model of Apis mellifera nAChR namely, Amelα8/β2 (b) The residues labeled in black are in the α chain, while the other residues labeled in cyan are in the β chain of Amelα8/β2. Imidacloprid and phenylacetohydrazone compound VS-04 are shown as stick models in yellow and pink, respectively. The cyan-dotted line indicates the H-bond interaction between the ligand and the receptor

Scheme 1. Synthetic route for the preparation of target compounds 3a~3v and their precursors (1a~1v and 2a~2v) Reagents and conditions: (i) EtOH, SOCl2, reflux, 2 h; (ii) EtOH, NH2NH2•H2O, reflux, 5 h; (iii) EtOH, reflux, 1 h

No.	X	R	n	(Mortality rate±St. D^a)/%
3a	CH	H	0	32.32±3.16
3b	CH	H	1	65.40±3.67
3c	CH	4-CH₃	1	71.86±2.93
3d	CH	4-C₆H₅	1	73.44±2.19
3e	CH	4-F	1	70.16±1.22
3f	CH	2-F	1	70.72±1.88
3g	CH	2-CH₃	1	53.77±3.05
3h	CH	3-F	1	43.69±3.48
3i	CH	3-OCH₃	1	41.74±4.34
3j	CH	4-CF₃	1	28.52±2.12
3k	CH	4-OCH₃	1	36.09±1.93
3l	CH	4-OH	1	54.75±4.60
3m	CH	4-Br	1	29.39±5.92
3n	CH	2,5-(CH₃)₂	1	27.38±6.35
3o	CH	3,5-(OCH₃)₂	1	19.89±3.59
3p	CH	3-CF₃	1	16.05±1.34
3q	CH	2,6-Cl₂	1	15.93±3.06
3r	CH	3-Cl	1	25.86±1.91
3s	CH	4-NO₂	1	15.61±1.47
3t	CH	4-Cl	1	11.01±3.52
3u	CH	2,4-F	1	60.22±1.06
3v	N	H	1	65.65±0.90
Imidacloprid				92.40±2.34

Table 1. Mortality rate against soybean aphids of the newly synthesized phenylacetohydrazone compounds 3a~3v at the concentration of 500 μg/mL

Figure 2. X-ray diffraction crystal structure of newly synthesized phenylacetohydrazone compound 3m

Figure 3. Electron density of imidacloprid (a) and newly synthesized phenylacetohydrazone compound 3c which shows good insecticidal activity (b)

No.	LD₅₀/(μg•bee^–1)	Equation	R²	95% CI^a
3c	30.35	y=–1.829+1.234lgx	0.944	23.075~44.696
3e	124.4	y=–2.458+1.174lgx	0.937	86.668~220.656
Imidacloprid	0.019/0.081^[23]	y=3.582+2.076lgx	0.992	0.011~0.028

Table 2. 48 h-Contact toxicity (LD50) on honeybees of the newly synthesized phenylacetohydrazone compounds 3c,3eand imidacloprid

Figure 4. Mode of action of newly synthesized phenylacetohydrazone compound 3c to honeybee AmeIα8/ratβ2

Figure 5. Further modification of the phenylacetohydrazone compound 3e which showed high mortality rate against soybean aphids

Scheme 2. Synthetic route for the preparation of target compounds 4a~4o

Figure 6. X-ray diffraction crystal structure of the newly synthesized phenylacetohydrazone compound 4h

Figure 7. Mode of action of the newly synthesized phenylacetohydrazone compound 4o to Ac-AChBP

No.	R	X	(Mortality rate±St. D^a)/%
4a	4-OCH₃	CH	29.37±1.61
4b	2,6-Cl	CH	53.73±8.50
4c	3-Br	CH	51.95±0.00
4d	4-NO₂	CH	50.17±4.71
4e	4-CH(CH₃)₂	CH	24.44±7.66
4f	4-Cl	CH	70.25±2.10
4g	H	N	82.63±5.70
4h	4-CF₃	CH	42.65±1.31
4i	4-Br	CH	43.98±6.12
4j	3-Cl	CH	66.53±10.64
4k	3-F	CH	46.81±4.31
4l	4-CH₃	CH	54.12±4.50
4m	4-F	CH	57.70±8.88
4n	H	CH	20.85±2.92
4o	2-Cl	CH	75.08±6.23
Imidacloprid			92.88±2.36

Table 3. Mortality rate against soybean aphids of the newly synthesized phenylacetohydrazone compounds 4a~4o at concentration of 500 μg/mL

No.	LC₅₀/(μg•mL^–1)	Equation	R²	95% CI^a
3e	147.30	y=–2.904+1.339lgx	0.988	110.82~208.096
4f	83.42	y=–2.626+1.367lgx	0.938	36.851~229.430
4g	66.44	y=–2.443+1.340lgx	0.985	50.397~88.129
Imidacloprid	29.87	y=–2.406+1.631lgx	0.930	13.787~54.372

Table 4. LC50 value against soybean aphids of the newly synthesized phenylacetohydrazone compounds 3e, 4f, 4g and imidacloprid

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基于昆虫nAChR选择性的新型低蜂毒苯乙酰腙类似物的筛选和优化

Screening and Optimization of Novel Low Bee-Toxicity Phenylace- tohydrazone Compounds Based on Insect nAChR Selectivity

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