含苯丙氨酸和1<i>H</i>-茚-1-酮类氯虫苯甲酰胺类似物的合成及杀虫活性

方佳琪; 郝树林; 杜晓华

doi:10.16801/j.issn.1008-7303.2022.0030

含苯丙氨酸和1H-茚-1-酮类氯虫苯甲酰胺类似物的合成及杀虫活性

doi: 10.16801/j.issn.1008-7303.2022.0030

1.
浙江工业大学催化加氢中心，浙江省绿色农药清洁生产技术研究重点实验室，浙江省绿色农药协同创新中心，杭州 310014

基金项目: 国家重点研发计划 (2016YFD0300708).

详细信息

作者简介:
方佳琪，1641254318@qq.com

通讯作者:
杜晓华，duxiaohua@zjut.edu.cn

中图分类号: O626.2；TQ455.4
计量
- 文章访问数: 56
- HTML全文浏览量: 22
- PDF下载量: 13
- 被引次数: 0
出版历程
- 收稿日期: 2021-11-23
- 录用日期: 2022-03-01
- 网络出版日期: 2022-03-29
- 刊出日期: 2022-08-03

Synthesis and insecticidal activity of chlorantraniliprole analogs containing phenylalanine and 1H-inden-1-one

1.
Catalytic Hydrogenation Research Center, Zhejiang University of Technology, Zhejiang Key Laboratory of Green Pesticides and Cleaner Production Technology, Zhejiang Green Pesticide Collaborative Innovation Center, Hangzhou 310014, China

Funds: the National Key R&D Program (2016YFD0300708).

摘要

摘要: 为了开发新的杀虫化合物，以氯虫苯甲酰胺为先导，2-甲基-3-氨基苯甲酸为起始原料，经过卤化生成5-氯-3-甲基-2-氨基苯甲酸；再与3-溴-1-(3-氯吡啶-2-吡啶基)-1H-吡唑-5-甲酸进行缩合反应，生成6-氯-2-(3-溴-1-(3-氯吡啶-2-吡啶基)-1H-吡唑-5-基)-8-甲基-4H-3,1-苯并噁嗪-4-酮；最后引入苯丙氨酸片段并经环化反应，分别合成了两个系列共计23 个新化合物( 4 和 5 )，其中化合物 4 为含苯丙氨酸的氯虫苯甲酰胺类似物，化合物 5 为由化合物4环化生成的含1H-茚-1-酮片段的氯虫苯甲酰胺类似物，所有化合物的结构均通过核磁共振氢谱(¹H NMR)、碳谱(¹³C NMR)和高分辨质谱(HRMS)的表征及确证。初步室内杀虫活性测试结果表明，多数目标化合物对黏虫Mythinma separata具有较高的杀虫活性，其中14个化合物在100 mg/L下对黏虫Mythinma separata的致死率为100%，化合物 5k ( 1H-茚-1-酮片段中取代基为羟基 ) 在4和0.8 mg/L下的致死率分别为90%和70%，其LC₅₀值为0.55 mg/L。分子对接结果表明，化合物 5k 与氯虫苯甲酰胺一样，也是作用于鱼尼汀受体(RyR)，但与靶标结合的氨基酸残基不同，这种差异可能对黏虫的抗药性治理研究有益。
- 1H-茚-1-酮 /
- 氯虫苯甲酰胺 /
- 苯丙氨酸 /
- 黏虫 /
- 杀虫活性
Abstract: In order to develop new insecticidal compounds with chlorantraniliprole as the lead, 2-methyl-3-aminobenzoic acid was used as the starting material, which was halogenated to generate 5-chloro-3-methyl-2-aminobenzoic acid; and then it was condensed with 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid to give 2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-6-chloro-8-methyl-4H-benzo[d][1,3]oxazin-4-one; finally, a phenylalanine fragment was introduced and cyclized to synthesize two series of 23 new compounds ( 4 and 5 ), compound 4 was chlorantraniliprole analog containing phenylalanine, and compound 5 was chlorantraniliprole analog containing 1H-inden-1-one fragment cyclized by compound 4 . The structures of all compounds were characterized and confirmed by proton nuclear magnetic resonance spectroscopy (¹H NMR), carbon spectroscopy (¹³C NMR) and high resolution mass spectrometry (HRMS). The preliminary indoor insecticidal activity tests showed that most target compounds had high insecticidal activity against oriental armyworm, Mythinma separata, with 14 compounds had 100% mortalities against M. separata at 100 mg/L, and compound 5k (the substituent in the 1H-inden-1-one fragment was hydroxyl) had 90% and 70% mortalities at 4 mg/L and 0.8 mg/L, respectively. And its LC₅₀ value was 0.55 mg/L. In addition, molecular docking results showed that compound 5k also acted on ryanodine (RyR), just like chlorantraniliprole, but the amino acid residues bound to the target were different, which might be beneficial for research on drug resistance management of oriental armyworm.
- 1H-inden-1-one /
- chlorantraniliprole /
- phenylalanine /
- Mythinma separata /
- insecticidal activity

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1 目标化合物的设计策略

1. Design strategy of target compounds

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2 目标化合物4和5的合成路线

2. Synthetic routes of target compounds 4 and 5

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3 成环反应过程

3. Ring-forming reaction process

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图 1 氯虫苯甲酰胺与RyR N端结构域之间的理论结合模式

Figure 1. Theoretical binding mode between chlorantraniliprole and N-terminal domain of RyR

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图 2 5k与RyR N端结构域之间的理论结合模式

Figure 2. Theoretical binding mode between 5k and N-terminal domain of RyR

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表 1 目标化合物对黏虫的杀虫活性

Table 1. Insecticidal activities of the target compounds against oriental armyworm

化合物 Compd.	死亡率 Mortality/%
	质量浓度 Mass concentration/(mg/L)
	100	20	4	0.8
4a	100	100	60	30
4b	100	60	10	0
4c	100	70	0	0
4d	90	80	50	0
4e	100	90	50	0
4f	100	90	30	0
4g	100	80	0	0
4h	100	70	50	20
4i	0	—	—	—
4j	0	—	—	—
4k	100	80	60	0
4l	100	80	0	0
5a	100	0	0	0
5b	0	—	—	—
5c	100	90	60	20
5d	0	—	—	—
5e	0	—	—	—
5f	90	30	0	0
5g	100	70	50	10
5h	100	80	50	10
5i	100	100	70	0
5j	0	—	—	—
5k	100	100	90	70
氯虫苯甲酰胺 chlorantraniliprole	100	100	90	80
CK	0	0	0	0
注：表中“—”为未测定。Note: "—" in the table means not determined.

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表 2 部分目标化合物的LC₅₀值

Table 2. The LC₅₀ value of some target compounds (95% confidence limit)

化合物 Compound	回归方程 Regression equation	相关系数 r	LC₅₀值 (95% 置信限) LC₅₀ value (95% confidence limit)/ (mg/L)
4a	y = 3.8452 + 2.3618x	0.9900	3.80 (2.52~3.86)
5i	y = 4.1824 + 2.2863x	0.9907	2.28 (1.83~2.80)
5k	y = 0.5531 + 2.2629x	0.9936	0.55 (0.45~0.69)
氯虫苯甲酰胺 chlorantraniliprole	y = 0.5423 + 2.2527x	0.8974	0.54 (0.44~0.71)

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