2-芳基-3, 4-二氢异喹啉类植物源抑菌剂的设计合成及构效关系研究

引用本文: 陈伟, 左怀龙, 李玉新, 刘江, 周先礼. 2-芳基-3, 4-二氢异喹啉类植物源抑菌剂的设计合成及构效关系研究[J]. 有机化学, 2019, 39(8): 2317-2322. doi: 10.6023/cjoc201905020 shu

Citation: Chen Wei, Zuo Huailong, Li Yuxin, Liu Jiang, Zhou Xianli. Design, Synthesis and Structure-Activity Relationships of Plant-Based 2-Aryl-3, 4-dihydroisoquinolin-2-iums as Potential Antifungal Agents[J]. Chinese Journal of Organic Chemistry, 2019, 39(8): 2317-2322. doi: 10.6023/cjoc201905020 shu

2-芳基-3, 4-二氢异喹啉类植物源抑菌剂的设计合成及构效关系研究

陈伟 ^{a,
,} ,
左怀龙 ^a, ,
李玉新 ^b, ,
刘江 ^a, ,
周先礼 ^a,

a.
西南交通大学生命科学与工程学院成都 610031
b.
南开大学元素有机化学国家重点实验室天津 300071

通讯作者: 陈伟, chenweicstq@163.com

基金项目:
国家自然科学基金（No.21702173）、中央高校基本科研业务费（No.2682016CX104）和四川省科技创新苗子工程（No.2682017QY04）资助项目

摘要: 植物病原菌严重危及农作物的生产安全.为了寻找新型的抑菌剂，通过合理的分子拼接，将苯甲酸类和苯酚类药效团引入异喹啉的2-位，设计并合成了15个2-芳基-3，4-二氢异喹啉衍生物，利用核磁共振和高分辨质谱鉴定了化合物结构.初步离体抑菌结果显示，大部分化合物对11种受试植物病原菌都具有中等到显著的抑制活性，与阳性对照样（百菌清、多菌灵）相当.2-（3-乙氧羰基苯基）-3，4-二氢异喹啉溴化盐（4j）对水稻纹枯病菌的EC₅₀为3.8495 mg·mL^-1，优于对照样百菌清（4.6328 mg·mL^-1）.其中有5个化合物对小麦纹枯病菌的EC₅₀（7.4583~15.4495 mg·mL^-1）都优于百菌清（16.0137 mg·mL^-1），其中2-（4-甲氧羰基苯基）-3，4-二氢异喹啉溴化盐（4f）最为显著，为植物源抑菌剂的开发提高了理论基础.

关键词:

English

Design, Synthesis and Structure-Activity Relationships of Plant-Based 2-Aryl-3, 4-dihydroisoquinolin-2-iums as Potential Antifungal Agents

a.
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031
b.
State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071

Corresponding author: Chen, Wei, E-mail: chenweicstq@163.com

Received Date: 10 May 2019
Revised Date: 02 June 2019
Available Online: 25 August 2019
Fund Project:
Project supported by the National Natural Science Foundation of China (No. 21702173), the Fundamental Research Funds for the Central Universities (No. 2682016CX104) and the Miaozi Project of Scientific and Technological Innovation of Sichuan Province (No. 2018090)

Abstract: In order to discover more potent antifungal, a series of 2-aryl-3, 4-dihydroisoquinolin-2-iums were reasonable designed and productive synthesized by introducing benzoic acid and phenol pharmacophores into the 2-position of isoquinoline. Their structures were identified by NMR and HRMS. The preliminary in vitro antifungal results showed that most of the title compounds exhibited moderate to significant inhibitory activities against various phytopathogenic fungi at 50 mg·mL^-1, and were equal to controls (chlorothalonil, carbendazim). The concentration of 50% inhibition rate (EC₅₀) of 2-(3-ethoxycarbonyl-phenyl)-3, 4-dihydroisoquinolin-2-ium (4j) against R. solani was 3.8495 mg·mL^-1, which was significantly superior to chlorothalonil (4.6328 mg·mL^-1). All the EC₅₀ values of 5 compounds (7.4583~15.4495 mg·mL^-1) against R. cerealis were better than chlorothalonil (16.0137 mg·mL^-1), and 2-(4-methoxycarbonylphenyl)-3, 4-dihydroisoquinolin-2-ium (4f) is the best one. The present results provide valuable information for development of plant-based antifungal agents.

Key words:

由植物病原菌引起的植物病害是农作物生产中的主要危害, 通常会导致农产品产量和质量显著下降, 并造成巨大的经济损失^[1~3].同时, 一些植物病原菌还能产生真菌毒素危及人类和动物健康^{[4, 5]}.然而, 植物病原菌的防治仍是一个难题, 商用化学杀菌剂并没有完全有效.此外, 随着农用化学品的普遍应用, 农药残留、农药抗性和环境污染已成为一个严重问题^{[6, 7]}.因此, 开发新型的抑菌剂来有效控制植物病害具有重要的应用价值.

植物源抑菌剂因环境兼容性好, 对哺乳动物低毒等特点, 受到了研究者的高度重视^{[8, 9]}.血根碱(Sanguinarine)和白屈菜红碱(Chelerythine)是季铵盐型苯并菲啶生物碱(QBA_S)典型代表(图 1), 具有显著抗微生物病原体活性^{[10, 11]}. Zhou等研究指出C＝N⁺是QBA_S的关键药效团, 利用骨架跃迁的原理, 设计并合成了系列2-芳基-3, 4-二氢异喹啉衍生物(ADHIQs), 大部分化合物的抑菌活性优于先导物血根碱和白屈菜碱^{[12, 13]}.因此, ADHIQs可以作为一个理想的QBA_S模型物, 进行植物源抑菌剂研究.

图 1

图 1. 模型化合物2-芳基-3, 4-二氢异喹啉衍生物(ADHIQs)的由来

Figure 1. rigin of lead compounds 2-aryl-3, 4-dihydroiso-quinolin-2-ium (ADHIQs)

下载: 全尺寸图片幻灯片

苯甲酸类和苯酚类结构单元广泛存在于植物次生代谢产物中, 也是医药和农用化学品中重要的药效基团, 氟吗啉、嘧菌酯和申嗪霉素等都是含有这类结构单元的抑菌剂^{[14, 15]}.由于其显著的药理活性, 针对这类药效基团的研究一直受到研究者的重视.为了更加深入的研究ADHIQs, 寻找理想的植物源抑菌剂.本文结合前期的研究基础, 利用药效团拼接, 将苯甲酸类和苯酚类药效团引入异喹啉的N位, 设计并合成了一系列ADHIQs 4a~4o (图 2), 并测试了目标化合物对11种植物病原菌的抑菌活性.

图 2

图 2. 目标化合物4a~4o的设计

Figure 2. Design of title compounds 4a~4o

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1. 结果与讨论

1.1 中间体和目标化合物的合成

本文以异色满1为起始原料, 经溴化铜催化一步高效地制备关键中间体2-溴乙基苯甲醛(2), 然后与取代苯胺3在冰浴冷却下反应生成活性中间体亚胺, 进一步发生分子内的环合得到目标化合物4a~4o (Scheme 1).在NMR谱图中, 存在CH＝N⁺的特征信号峰(δ_H＞9, s, 1H; δ_C＞160);经HRMS检测, ESI⁺模式下可见[M-Br^-]⁺峰, 表明目标化合物为季亚胺异喹啉形式.

图式 1

图式 1. 目标化合物4a~4o的合成路线

Scheme 1. Synthetic route of title compounds 4a~4o

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1.2 目标化合物的抑菌活性

初步离体抑菌结果显示(表 1), 在50 mg·L^-1的处理浓度下, 大部分化合物都具有中等到优异的抑菌活性, 与阳性对照样(百菌清和多菌灵)接近或相当.对于所有受试菌种, 至少有4种目标化合物对其抑制活性大于60%.其中, 4a~4c, 4f和4i~4k对7种及以上病原菌的抑制率在60.0%以上.尤其是4a, 4f, 4j, 4k和4n对水稻纹枯病菌和小麦纹枯病菌的抑制率都高达98.0%以上; 4a对小麦赤霉病菌和玉米小斑病菌的抑菌活性为100.0%, 与对照样百菌清和多菌灵一致.对于花生褐斑病菌, 4a~4c, 4e, 4i和4k的抑制率大于60.0%, 优于阳性对照药(≤57.1%); 4a和4b对水稻恶苗病菌的活性(94.4%)优于对照样(≤87.5%).进一步EC₅₀测试结果表明(表 2), 4f, 4j, 4k, 4n对水稻纹枯病菌的EC₅₀为3.8495~10.7726 μg·mL^-1, 其中4j (3.8495 μg·mL^-1)优于对照样百菌清(4.6328 μg·mL^-1), 4f (EC₅₀＝5.0256 μg·mL^-1)与百菌清接近. 4f, 4i~4k和4n对小麦纹枯病菌的EC₅₀ (7.4583~15.4495 μg·mL^-1)都优于百菌清(16.0137 μg·mL^-1), 4f最为显著.

表 1

表 1 目标化合物4a~4o的离体抑菌活性(50 mg·L^-1, %)

Table 1. In vitro antifungal activities of target compound 4a~4o (50 mg·L^-1, %)

下载: 导出CSV

No.	AS^a	FG	PC	SS	RS	CC	PP	FM	HM	CL	RC
4a	61.1	100.0	69.2	29.5	99.8	68.4	93.5	94.4	97.0	100.0	98.2
4b	35.7	75.0	41.9	21.2	68.8	63.2	90.3	94.4	97.0	96.8	86.0
4c	42.9	75.0	58.1	69.2	50.0	63.2	80.6	77.8	66.7	71.0	89.5
4d	35.7	50.0	9.7	50.0	65.6	52.6	71.0	66.7	45.5	64.5	89.5
4e	22.2	10.7	88.5	29.5	12.9	60.9	64.5	33.3	42.4	41.9	80.7
4f	63.6	30.8	67.7	66.7	100.0	57.1	100.0	62.5	66.7	64.7	100.0
4g	54.5	53.8	22.6	44.4	60.7	35.7	50.0	31.3	22.2	17.6	38.5
4h	36.4	69.2	45.2	50.0	71.4	50.0	73.1	56.3	55.6	35.3	92.3
4i	72.7	19.2	67.7	100.0	80.4	71.4	84.6	75.0	77.8	64.7	100.0
4j	72.7	57.7	67.7	72.2	100.0	42.9	88.5	68.8	61.1	47.1	100.0
4k	72.7	46.2	54.8	55.6	100.0	64.3	92.3	68.8	66.7	35.3	100.0
4l	36.4	38.5	16.1	66.7	53.6	42.9	84.6	31.3	44.4	17.6	38.5
4m	27.3	23.1	9.7	27.8	53.6	7.1	19.2	25.0	22.2	5.9	38.5
4n	72.7	34.6	51.6	83.3	100.0	57.1	53.8	56.3	50.0	23.5	100.0
4o	18.2	38.5	25.8	72.2	42.9	28.6	76.9	25.0	50.0	23.5	15.4
CH^b	90.9	57.7	80.6	100.0	91.1	57.1	92.3	87.5	72.2	70.6	100.0
CA^b	54.5	100.0	48.4	100.0	100.0	21.4	92.3	81.3	100.0	100.0	100.0
^a AS: Alternaria solani, FG: Fusahum graminearum, PC: Phytophthora capsici, SS: Sclerotinia sclerotiorum, RS: Rhizoctonia solani, CC: Cercosporaara chidicola, PP: Physalospora piricola, FM: Fusarium moniliforme Sheld, HM: Helminthosporium maydis Nisik & Miy, CL: Colletotrichum lagenarium, RC: Rhizotonia cerealis. ^b CH: Chlorothalonil, CA: Carbendazim.

表 2

表 2 部分化合物对水稻纹枯病菌和小麦纹枯病菌的EC₅₀ (μg·mL^-1)

Table 2. EC₅₀ (μg·mL^-1) of some compounds against R. solani and R. cerealis

下载: 导出CSV

No.	R. solani			R. cerealis
No.	EC₅₀	Toxic regression equation	r	EC₅₀	Toxic regression equation	r
4f	5.0256	y＝2.0389x+3.5703	0.9709	7.4583	y＝2.4912x+3.2577	0.9989
4i	—	—	—	10.8475	y＝2.4888x+2.6024	0.9984
4j	3.8495	y＝1.5781x+4.0761	0.9835	10.0970	y＝2.8167x+2.4458	0.9879
4k	9.3223	y＝2.6780x+2.4036	0.9730	15.4495	y＝2.7646x+2.1142	0.9986
4n	10.7726	y＝2.9948x+1.9084	0.9829	13.3171	y＝2.8105x+2.1487	0.9976
CH^a	4.6328	y＝2.1850x+3.5451	0.9933	16.0137	y＝2.5731x+2.1887	0.9960
^a CH: Chlorothalonil.

与文献[12, 13, 17]对比研究表明, 季亚胺异喹啉是关键母核, 异喹啉2-位为苯酚类药效团或者苯甲酸类药效团时都有助于抑菌活性, 并且苯环上取代基R的种类、位置对植物病菌的活性和抑菌谱有显著影响. (1)在苯酚类药效团衍生物中, 含有弱吸电子基团有利于抑菌活性[4a (2-OH-5-Cl)＞4b (2-OH-5-Br)＞＞4c (2-OH-5-NO₂)]. (2)在苯甲酸类药效团中, 苯甲酸酯衍生物的活性优于苯甲酸[4f (4-COOCH₃)≈4i (4-COOC₄H₉)＞4e (4-COOH)]. (3)当取代基R为单酯时, R位于苯环的3/4位, 有助于抑菌活性[4f (4-COOCH₃)≈4i (4-COOC₄H₉)＞4h (3-COOCH₃)＞4g (2-COOCH₃)]. (4)当R为单酯取代基或者双酯时, 抑菌活性无明显区别[4k (3, 5-(COOCH₃)₂)与4h, 4l (2, 5-(COOCH₃)₂)与4g]. (5)酯基中烷基的大小对活性无显著影响(4f与4i, 4h与4j).总体表明, 在异喹啉的N位引入苯酚类和苯甲酸类药效团可提高化合物的抑菌活性.在苯酚类药效团衍生物中(4a~4d), 苯环上有弱吸电基团有利于抑菌活性和抑菌广谱性; 而对于苯甲酸类药效团衍生物(4e~4o), 取代基R位于苯环3/4位更优.

2. 结论

本文通过合理的分子拼接, 将苯酚类和苯甲酸类药效团引入异喹啉的2-位, 设计并合成了15个2-芳基-3, 4-二氢异喹啉衍生物4a~4o, 利用NMR和HRMS鉴定了其结构.在50 mg·L^-1的测试浓度下, 大部分化合物都具有中等到优异的离体抑菌活性, 并且部分化合物与对照样百菌清和多菌灵相当. 4a, 4f, 4j, 4k和4n对水稻纹枯病菌和小麦纹枯病菌的抑制率高达98.0%以上, 其中4j (EC₅₀＝3.8495 μg·mL^-1)对水稻纹枯病菌的EC₅₀优于对照样百菌清(4.6328 μg·mL^-1); 4f, 4i~4k和4n对小麦纹枯病菌的EC₅₀ (7.4583~15.4495 μg·mL^-1)都优于百菌清(16.0137 μg·mL^-1), 4f最为显著.研究结果表明, 在异喹啉2-位引入苯酚类药效团或者苯甲酸类药效团时都有助于抑菌活性, 为新型植物源抑菌剂的创制提供了理论基础.

3. 实验部分

3.1 仪器和试剂

600/400 MHz核磁共振仪(Brucker AV 600/400, Bruker), CDCl₃和DMSO-d₆为溶剂, TMS为内标. Xevo G2-S Tof型高分辨质谱仪(Waters).所用试剂均为市售化学纯或分析纯试剂, 用前无需进行处理.

3.2 化合物的合成

3.2.1 中间体2-溴乙基苯甲醛2的合成

将异色满1 (0.05 mol, 6.71 g)和溴化铜(0.06 mol, 13.4 g)溶于80 mL乙腈中, 氮气保护下加热至回流, 薄层色谱板(TLC)监测至反应完全.冷却后减压脱除溶剂, 向残余物中加入100 mL乙酸乙酯, 饱和食盐水洗涤至中性, 无水硫酸钠干燥, 柱层析分离得无色液体2^[16], 产率92.6%. ¹H NMR (400 MHz, CDCl₃) δ: 10.16 (s, 1H), 7.40~7.35 (m, 1H), 7.34~7.25 (m, 3H), 4.01 (t, J＝5.7 Hz, 2H), 2.90 (t, J＝5.7 Hz, 2H).

3.2.2 目标化合物4a~4o的合成

以化合物4a合成为例.将1.0 mmol的2-氨基-4-氯苯酚3a溶于10 mL乙腈中, 冰浴冷却, 滴加溶有2 (1.2 mmol)的乙腈(5 mL)溶液, 搅拌过夜.减压脱除溶剂, 向残余物中加入10 mL乙酸乙酯, 充分搅拌, 抽滤, 固体用乙酸乙酯洗涤, 烘干得目标化合物4a.其余目标化合物的合成方法与4a相同, 将反应底物2-氨基-4-氯苯酚替换为各种取代的苯胺3b~3o.

2-(4-氯-2-羟基苯基)-3, 4-二氢异喹啉溴化盐(4a):浅褐色固体, 产率81.2%. m.p. 216~219 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.36 (s, 1H), 9.61 (s, 1H), 8.01 (d, J＝7.5 Hz, 1H), 7.94~7.90 (m, 2H), 7.67~7.59 (m, 2H), 7.53 (dd, J＝8.8, 2.6 Hz, 1H), 7.21 (d, J＝8.9 Hz, 1H), 4.41 (t, J＝7.8 Hz, 2H), 3.39 (t, J＝7.8 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.33, 150.31, 139.18, 137.80, 135.30, 132.30, 131.41, 128.94, 128.83, 126.28, 125.68, 123.10, 119.26, 51.81, 25.42. HRMS (ESI) calcd for C₁₅H₁₃ClNO [M-Br^-]⁺ 258.0686, found 258.0680.

2-(4-溴-2-羟基苯基)-3, 4-二氢异喹啉溴化盐(4b):褐色固体, 产率84.1%. m.p. 210~213 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.40 (s, 1H), 9.59 (s, 1H), 8.01 (dd, J＝8.4, 5.0 Hz, 2H), 7.91 (t, J＝7.4 Hz, 1H), 7.67~7.57 (m, 3H), 7.18~7.13 (m, 1H), 4.40 (t, J＝7.8 Hz, 2H), 3.38 (t, J＝7.8 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.30, 150.74, 139.17, 137.80, 135.29, 135.15, 131.84, 128.97, 128.93, 128.83, 125.68, 119.68, 110.25, 51.81, 25.42. HRMS (ESI) calcd for C₁₅H₁₃BrNO [M-Br^-]⁺ 302.0181, found 302.0190.

2-(2-羟基-4-硝基苯基)-3, 4-二氢异喹啉溴化盐(4c):褐色固体, 产率79.6%. m.p. 234~236 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.57 (s, 1H), 8.78 (d, J＝2.4 Hz, 1H), 8.35 (dd, J＝9.1, 2.7 Hz, 1H), 8.00 (d, J＝7.5 Hz, 1H), 7.90 (t, J＝7.4 Hz, 1H), 7.64~7.59 (m, 2H), 7.37 (d, J＝9.2 Hz, 1H), 4.41 (t, J＝7.7 Hz, 2H), 3.38 (t, J＝7.7 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 157.83, 139.69, 138.95, 137.91, 135.14, 130.89, 128.98, 128.79, 127.89, 125.99, 122.83, 122.77, 117.62, 51.39, 25.40. HRMS (ESI) calcd for C₁₅H₁₃N₂O₃ [M-Br^-]⁺ 269.0926, found 269.0926.

2-(4-溴-2-甲氧基苯基)-3, 4-二氢异喹啉溴化盐(4d):浅褐色固体, 产率89.6%. m.p. 201~203 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.58 (s, 1H), 8.01 (d, J＝7.5 Hz, 1H), 7.92 (td, J＝7.6, 1.1 Hz, 1H), 7.78 (d, J＝8.4 Hz, 1H), 7.69~7.57 (m, 3H), 7.46 (dd, J＝8.4, 1.9 Hz, 1H), 4.38 (t, J＝7.8 Hz, 2H), 3.97 (s, 3H), 3.39 (t, J＝7.8 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.43, 153.44, 139.25, 137.86, 135.34, 131.30, 128.96, 128.85, 127.99, 125.70, 125.63, 124.45, 117.16, 57.75, 52.06, 25.42. HRMS (ESI) calcd for C₁₆H₁₅BrNO [M-Br^-]⁺ 316.0337, found 316.0350.

2-(4-羧基苯基)-3, 4-二氢异喹啉溴化盐(4e):浅黄色固体, 产率69.8%. m.p. 211~214 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 13.40 (br, 1H), 9.80 (s, 1H), 8.20 (d, J＝8.6 Hz, 2H), 8.08 (d, J＝7.4 Hz, 1H), 8.02 (d, J＝8.2 Hz, 2H), 7.91 (t, J＝7.4 Hz, 1H), 7.65~7.61 (m, 2H), 4.63 (t, J＝7.8 Hz, 2H), 3.44 (t, J＝7.9 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.37, 166.62, 146.34, 139.21, 137.84, 135.63, 133.09, 131.26, 128.80, 126.04, 123.62, 51.09, 25.32. HRMS (ESI) calcd for C₁₆H₁₄NO₂ [M-Br^-]⁺ 252.1025, found 252.1042.

2-(4-甲氧羰基苯基)-3, 4-二氢异喹啉溴化盐(4f):黄色固体, 产率91.2%. m.p. 191~193 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.80 (s, 1H), 8.24 (d, J＝8.7 Hz, 2H), 8.09~8.04 (m, 3H), 7.93 (t, J＝7.3 Hz, 1H), 7.67~7.62 (m, 2H), 4.64 (t, J＝7.8 Hz, 2H), 3.93 (s, 3H), 3.45 (t, J＝7.8 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.54, 165.60, 146.61, 139.27, 137.88, 135.68, 131.81, 131.17, 128.80, 126.02, 125.95, 123.78, 53.15, 51.07, 25.32. HRMS (ESI) calcd for C₁₇H₁₆NO₂ [M-Br^-]⁺ 266.1181, found 266.1204.

2-(2-甲氧羰基苯基)-3, 4-二氢异喹啉溴化盐(4g):黄色固体, 产率60.3%. m.p. 144~146 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.85 (s, 1H), 8.49 (dd, J＝7.9, 0.8 Hz, 1H), 8.36 (d, J＝7.1 Hz, 1H), 8.18 (dd, J＝7.9, 1.4 Hz, 1H), 7.82 (td, J＝7.8, 1.5 Hz, 1H), 7.74 (td, J＝7.6, 1.1 Hz, 1H), 7.65 (td, J＝7.8, 1.0 Hz, 1H), 7.48 (t, J＝7.6 Hz, 1H), 7.39 (d, J＝7.6 Hz, 1H), 4.42 (br, 2H), 3.89 (s, 3H), 3.61 (br, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 168.56, 164.32, 142.45, 138.79, 136.75, 136.45, 135.43, 132.22, 131.51, 128.72, 128.19, 128.01, 125.30, 124.00, 53.98, 53.03, 26.20. HRMS (ESI) calcd for C₁₇H₁₆NO₂ [M-Br^-]⁺ 266.1181, found 266.1204.

2-(3-甲氧羰基苯基)-3, 4-二氢异喹啉溴化盐(4h):黄色固体, 产率80.9%. m.p. 184~186 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 10.37 (s, 1H), 8.57 (dd, J＝8.1, 1.7 Hz, 1H), 8.44 (d, J＝7.4 Hz, 1H), 8.37 (s, 1H), 8.14 (d, J＝7.9 Hz, 1H), 7.75 (td, J＝7.6, 1.0 Hz, 1H), 7.66 (t, J＝8.0 Hz, 1H), 7.48~7.41 (m, 1H), 4.65 (t, J＝7.9 Hz, 2H), 3.92 (s, 3H), 3.57 (t, J＝7.9 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 166.69, 165.22, 142.58, 139.05, 136.79, 136.45, 132.00, 131.81, 130.94, 128.83, 128.18, 127.87, 125.67, 123.03, 52.78, 51.81, 25.92. HRMS (ESI) calcd for C₁₇H₁₆NO₂ [M-Br^-]⁺ 266.1181, found 266.1204.

2-(4-丁氧羰基苯基)-3, 4-二氢异喹啉溴化盐(4i):黄色固体, 产率87.4%. m.p. 155~157 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 10.48 (s, 1H), 8.39 (d, J＝7.4 Hz, 1H), 8.18 (d, J＝8.9 Hz, 2H), 8.12 (d, J＝8.8 Hz, 2H), 7.74~7.67 (m, 1H), 7.46~7.33 (m, 2H), 4.63 (t, J＝7.9 Hz, 2H), 4.32 (t, J＝6.6 Hz, 2H), 3.51 (t, J＝7.9 Hz, 2H), 1.80~1.70 (m, 2H), 1.55~1.40 (m, 2H), 0.98 (t, J＝7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 166.66, 164.90, 145.23, 139.26, 136.97, 136.65, 132.74, 131.51, 128.85, 128.20, 125.61, 123.05, 65.59, 51.76, 30.68, 25.93, 19.27, 13.79. HRMS (ESI) calcd for C₂₀H₂₂NO₂ [M-Br^-]⁺ 308.1651, found 308.1660.

2-(3-乙氧羰基苯基)-3, 4-二氢异喹啉溴化盐(4j):黄色固体, 产率84.1%. m.p. 182~185 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 10.38 (s, 1H), 8.62 (dd, J＝8.1, 1.7 Hz, 1H), 8.46 (d, J＝7.4 Hz, 1H), 8.32 (s, 1H), 8.16 (d, J＝7.9 Hz, 1H), 7.75 (dt, J＝7.6, 3.8 Hz, 1H), 7.67 (t, J＝8.0 Hz, 1H), 7.48 (t, J＝7.6 Hz, 1H), 7.42 (d, J＝7.6 Hz, 1H), 4.63 (t, J＝7.9 Hz, 2H), 4.40 (q, J＝7.1 Hz, 2H), 3.57 (t, J＝7.9 Hz, 2H), 1.42 (dd, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 166.71, 164.78, 142.62, 139.08, 136.85, 136.46, 132.42, 131.83, 130.97, 128.89, 128.22, 127.84, 125.71, 122.95, 61.96, 51.86, 25.97, 14.34. HRMS (ESI) calcd for C₁₈H₁₈NO₂ [M-Br^-]⁺ 280.1338, found 280.1354.

2-(3, 5-二甲氧羰基苯基)-3, 4-二氢异喹啉溴化盐(4k):黄色固体, 产率91.1%. m.p. 193~195 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 10.37 (s, 1H), 8.81 (d, J＝1.1 Hz, 2H), 8.76 (s, 1H), 8.39 (d, J＝7.6 Hz, 1H), 7.76 (t, J＝7.5 Hz, 1H), 7.54~7.39 (m, 2H), 4.64 (t, J＝7.8 Hz, 2H), 3.95 (s, 6H), 3.60 (t, J＝7.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 167.22, 164.56, 143.15, 139.15, 136.77, 136.65, 132.77, 132.32, 128.87, 128.27, 127.88, 125.86, 53.04, 51.99, 26.00. HRMS (ESI) calcd for C₁₉H₁₈NO₄ [M-Br^-]⁺ 324.1236, found 324.1247.

2-(2, 5-二甲氧羰基苯基)-3, 4-二氢异喹啉溴化盐(4l):白色固体, 产率79.5%. m.p. 196~198 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 10.32 (s, 1H), 8.78 (s, 1H), 8.45 (d, J＝7.6 Hz, 1H), 8.30 (s, 2H), 7.79 (t, J＝7.5 Hz, 1H), 7.51 (t, J＝7.5 Hz, 1H), 7.44 (d, J＝7.6 Hz, 1H), 4.44 (br, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.63 (br, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 169.64, 164.38, 163.68, 142.31, 139.21, 136.99, 136.56, 135.99, 132.73, 132.29, 128.87, 128.35, 128.25, 128.12, 125.29, 53.88, 53.55, 53.18, 26.15. HRMS (ESI) calcd for C₁₉H₁₈NO₄ [M-Br^-]⁺ 324.1236, found 324.1247.

2-(4-氯-2-乙氧羰基苯基)-3, 4-二氢异喹啉溴化盐(4m):白色固体, 产率76.5%. m.p. 185~187 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.97 (s, 1H), 8.61 (s, 1H), 8.36 (d, J＝7.3 Hz, 1H), 8.15 (d, J＝8.4 Hz, 1H), 7.76 (t, J＝7.4 Hz, 1H), 7.62 (d, J＝8.3 Hz, 1H), 7.55~7.38 (m, 2H), 4.37 (br, 2H), 4.34 (q, J＝7.1 Hz, 2H), 3.64 (br, 2H), 1.34 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 169.08, 163.01, 142.92, 140.81, 139.07, 136.70, 133.32, 131.65, 128.60, 128.40, 128.36, 127.97, 125.11, 123.02, 62.53, 53.98, 26.13, 14.05. HRMS (ESI) calcd for C₁₈H₁₇ClNO₂ [M-Br^-]⁺ 314.0948, found 314.0956.

2-(3-羟基-4-甲氧羰基苯基)-3, 4-二氢异喹啉溴化盐(4n):黄色固体, 产率74.7%. m.p. 150~152 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.85 (s, 1H), 9.74 (s, 1H), 8.09~8.01 (m, 2H), 7.91 (s, 1H), 7.68~7.58 (m, 2H), 7.57~7.37 (m, 2H), 4.58 (s, 2H), 3.93 (s, 3H), 3.41 (s, 2H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 168.50, 168.16, 160.44, 147.82, 139.29, 137.95, 135.72, 135.10, 132.36, 128.78, 125.95, 116.17, 113.95, 112.38, 53.31, 50.90, 25.30. HRMS (ESI) calcd for C₁₇H₁₆NO₃ [M-Br^-]⁺ 282.1130, found 282.1149.

2-(4-羧基-2-甲基苯基)-3, 4-二氢异喹啉溴化盐(4o):白色固体, 产率81.3%. m.p. 280~282 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.62 (s, 1H), 8.08 (s, 1H), 8.05~8.01 (m, 2H), 7.95 (t, J＝7.6 Hz, 1H), 7.88 (d, J＝8.2 Hz, 1H), 7.66 (t, J＝7.0 Hz, 2H), 4.46 (t, J＝7.9 Hz, 2H), 3.48 (t, J＝7.9 Hz, 2H), 2.52 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.71, 166.72, 145.78, 139.30, 137.81, 135.44, 133.54, 133.31, 133.16, 128.96, 128.79, 128.76, 126.29, 125.75, 52.06, 25.35, 17.65. HRMS (ESI) calcd for C₁₇H₁₆NO₂ [M-Br^-]⁺ 266.1181, found 266.1204.

3.3 化合物的生物活性测试

3.3.1 抑菌活性测试

用平皿法^[1]测试了目标化合物4a~4o对番茄早疫病菌(A. solani), 小麦赤霉病菌(F. graminearum), 辣椒疫霉病菌(P. capsici), 油菜菌核病菌(S. sclerotiorum), 水稻纹枯病菌(R. solani), 花生褐斑病菌(C. chidicola), 苹果轮纹病菌(P. piricola), 水稻恶苗病菌(F. moniliforme), 玉米小斑病菌(H. maydis Nisik & Miy), 西瓜炭疽病菌(C. lagenarium)和小麦纹枯病菌(R. cerealis)共计11种常见病菌的离体抑菌活性, 百菌清和多菌灵为阳性对照药.在无菌条件下, 将化合物溶于二甲基亚砜中, 配成浓度为3.0×10⁴ mg·L的溶液, 用吐温溶液稀释成浓度500 mg·L的测试液.取1 mL上述溶液加入到9 mL马铃薯葡萄糖琼脂(PDA)培养基中, 待培养基完全凝固后接入供试菌种, 设置空白对照, 实验重复3次.在25±1 ℃下培养72 h后, 测量菌落直径, 并与空白对照组进行比较得到抑制率.

抑制率/%=(空白对照菌落增长直径-药剂处理菌落增长直径)/空白对照菌落增长直径×100%

抑制中浓度(EC₅₀)的测定:根据上述方法, 采用等倍稀释, 分别测试浓度为25, 12.5, 6.25, 3.125与1.56 μg· mL^-1时的抑制率, 然后用软件SPSS计算抑制中浓度EC₅₀.

辅助材料(SupportingInformation)目标化合物4a~4o的离体抑菌活性. ¹H NMR, ¹³C NMR和HRMS图谱.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.

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图 1 模型化合物2-芳基-3, 4-二氢异喹啉衍生物(ADHIQs)的由来

Figure 1 rigin of lead compounds 2-aryl-3, 4-dihydroiso-quinolin-2-ium (ADHIQs)

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图 2 目标化合物4a~4o的设计

Figure 2 Design of title compounds 4a~4o

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图式 1 目标化合物4a~4o的合成路线

Scheme 1 Synthetic route of title compounds 4a~4o

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表 1 目标化合物4a~4o的离体抑菌活性(50 mg·L^-1, %)

Table 1. In vitro antifungal activities of target compound 4a~4o (50 mg·L^-1, %)

No.	AS^a	FG	PC	SS	RS	CC	PP	FM	HM	CL	RC
4a	61.1	100.0	69.2	29.5	99.8	68.4	93.5	94.4	97.0	100.0	98.2
4b	35.7	75.0	41.9	21.2	68.8	63.2	90.3	94.4	97.0	96.8	86.0
4c	42.9	75.0	58.1	69.2	50.0	63.2	80.6	77.8	66.7	71.0	89.5
4d	35.7	50.0	9.7	50.0	65.6	52.6	71.0	66.7	45.5	64.5	89.5
4e	22.2	10.7	88.5	29.5	12.9	60.9	64.5	33.3	42.4	41.9	80.7
4f	63.6	30.8	67.7	66.7	100.0	57.1	100.0	62.5	66.7	64.7	100.0
4g	54.5	53.8	22.6	44.4	60.7	35.7	50.0	31.3	22.2	17.6	38.5
4h	36.4	69.2	45.2	50.0	71.4	50.0	73.1	56.3	55.6	35.3	92.3
4i	72.7	19.2	67.7	100.0	80.4	71.4	84.6	75.0	77.8	64.7	100.0
4j	72.7	57.7	67.7	72.2	100.0	42.9	88.5	68.8	61.1	47.1	100.0
4k	72.7	46.2	54.8	55.6	100.0	64.3	92.3	68.8	66.7	35.3	100.0
4l	36.4	38.5	16.1	66.7	53.6	42.9	84.6	31.3	44.4	17.6	38.5
4m	27.3	23.1	9.7	27.8	53.6	7.1	19.2	25.0	22.2	5.9	38.5
4n	72.7	34.6	51.6	83.3	100.0	57.1	53.8	56.3	50.0	23.5	100.0
4o	18.2	38.5	25.8	72.2	42.9	28.6	76.9	25.0	50.0	23.5	15.4
CH^b	90.9	57.7	80.6	100.0	91.1	57.1	92.3	87.5	72.2	70.6	100.0
CA^b	54.5	100.0	48.4	100.0	100.0	21.4	92.3	81.3	100.0	100.0	100.0
^a AS: Alternaria solani, FG: Fusahum graminearum, PC: Phytophthora capsici, SS: Sclerotinia sclerotiorum, RS: Rhizoctonia solani, CC: Cercosporaara chidicola, PP: Physalospora piricola, FM: Fusarium moniliforme Sheld, HM: Helminthosporium maydis Nisik & Miy, CL: Colletotrichum lagenarium, RC: Rhizotonia cerealis. ^b CH: Chlorothalonil, CA: Carbendazim.

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表 2 部分化合物对水稻纹枯病菌和小麦纹枯病菌的EC₅₀ (μg·mL^-1)

Table 2. EC₅₀ (μg·mL^-1) of some compounds against R. solani and R. cerealis

No.	R. solani			R. cerealis
No.	EC₅₀	Toxic regression equation	r	EC₅₀	Toxic regression equation	r
4f	5.0256	y＝2.0389x+3.5703	0.9709	7.4583	y＝2.4912x+3.2577	0.9989
4i	—	—	—	10.8475	y＝2.4888x+2.6024	0.9984
4j	3.8495	y＝1.5781x+4.0761	0.9835	10.0970	y＝2.8167x+2.4458	0.9879
4k	9.3223	y＝2.6780x+2.4036	0.9730	15.4495	y＝2.7646x+2.1142	0.9986
4n	10.7726	y＝2.9948x+1.9084	0.9829	13.3171	y＝2.8105x+2.1487	0.9976
CH^a	4.6328	y＝2.1850x+3.5451	0.9933	16.0137	y＝2.5731x+2.1887	0.9960
^a CH: Chlorothalonil.

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沈阳化工大学材料科学与工程学院沈阳 110142