含杂环1, 4-戊二烯-3-酮肟酯类化合物的合成及生物活性

引用本文: 夏丽娟, 王晓斌, 谢艳, 王晓燕, 肖维, 钟新敏, 黄民国, 薛伟. 含杂环1, 4-戊二烯-3-酮肟酯类化合物的合成及生物活性[J]. 应用化学, 2017, 34(3): 316-323. doi: 10.11944/j.issn.1000-0518.2017.03.160219 shu

Citation: XIA Lijuan, WANG Xiaobin, XIE Yan, WANG Xiaoyan, XIAO Wei, ZHONG Xinming, HUANG Minguo, XUE Wei. Synthesis and Biological Activity of Novel 1, 4-Pentadien-3-one Oxime Esters Bearing Heterocycle Moiety[J]. Chinese Journal of Applied Chemistry, 2017, 34(3): 316-323. doi: 10.11944/j.issn.1000-0518.2017.03.160219 shu

含杂环1, 4-戊二烯-3-酮肟酯类化合物的合成及生物活性

夏丽娟 ^a,b,‡, ,
王晓斌 ^a,‡, ,
谢艳 ^a, ,
王晓燕 ^c, ,
肖维 ^a, ,
钟新敏 ^a, ,
黄民国 ^a, ,
薛伟 ^{a,*,
,}

a.
贵州大学精细化工研究开发中心, 绿色农药与农业生物工程国家重点实验室培育基地, 教育部绿色农药与生物工程重点实验室贵阳 550025
b.
安顺市环境监测站贵州安顺 561000
c.
南京中医药大学第一临床医学院南京 210029

通讯作者: 薛伟, 教授; Tel/Fax:0851-88292920; E-mail:wxue@gzu.edu.cn; 研究方向:新农药和新医药的创制研究

基金项目:
贵州省优秀青年科技人才培养对象专项资金 No.201535

国家自然科学基金 No.21462012

贵州大学研究生创新基金 No.2016076
^‡ 作者夏丽娟和王晓斌对本研究工作具有同等贡献

摘要: 为创制具有较高生物活性的绿色农药，以姜黄素为先导，将具有良好生物活性的肟酯基团引入1，4-戊二烯-3-酮的骨架中，设计合成了一系列含杂环1，4-戊二烯-3-酮肟酯类化合物，其结构经红外光谱、核磁共振氢谱及碳谱和高分辨质谱确认。初步的生物活性测试结果表明，在药剂浓度为50 mg/L时，化合物5d对小麦赤霉病菌，水稻纹枯病菌和苹果腐烂病菌的抑制活性相对较好，分别为64.75%、52.05%和69.68%；在药剂浓度为500 mg/L时，化合物5d、5e和5f对TMV具有较好的治疗和钝化活性，其抑制率分别为56.93%和86.89%、53.08%和83.51%、53.40%和89.01%。以上研究结果表明，1，4-戊二烯-3-酮肟酯类化合物具有一定抑菌和抗病毒活性，在其结构基础上进行适当的改造，有望获得具有较高生物活性的有机分子。

关键词:

戊二烯-酮
/ 肟酯
/ 抑菌
/ 抗病毒

English

Synthesis and Biological Activity of Novel 1, 4-Pentadien-3-one Oxime Esters Bearing Heterocycle Moiety

a.
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Certer for Rearch and Development of Fine Chemicals, Guizhou University, Guiyang 550025, China
b.
Environmental Monitoring Station of Anshun, Anshun, Guizhou 561000, China
c.
the First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210029, China

Corresponding author: XUE Wei, professor; Tel/Fax:0851-88292920; E-mail:wxue@gzu.edu.cn; Research interests:design and development of novel pesticides and medicines

Received Date: 25 May 2016
Accepted Date: 09 August 2016
Revised Date: 13 July 2016
Available Online: 01 March 2017
Fund Project:
the Special Fund for Outstanding Scientific and Technological Candidates of Guizhou Province

Supported by the National Natural Science Foundation of China

the Innovation Fund for Graduate Student of Guizhou University
XIA Lijuan and WANG Xiaobin contributed equally to this work

Abstract: In order to explore novel green pesticide with potent biological activities, a series of novel 1, 4-pentadien-3-one oxime ester derivatives bearing heterocycle moiety, derived from curcumin, was designed and synthesized. Their structures were confirmed by infrared spectroscopy, proton nuclear magnetic resonance spectroscopy (¹H NMR), ¹³C NMR, and high resolution mass spectroscopy (HRMS). The bioassays indicate that inhibition rates of compound 5d against G.zeae, F.ox-ysporum and C.mandshurica at 50 mg/L are 64.75%, 52.05% and 69.68%, respectively, and compounds 5d, 5e and 5f have good curative and deactivation activities against tobacco mosaic virus at 500 mg/L, with the inhibition rates of 56.93% and 86.89%, 53.08% and 83.51%, and 53.40% and 89.01%, respectively. These indicate that 1, 4-pentadien-3-one oxime ester is a valuable scafford to develope new compounds poessessing high biological activities such as potential antifungal and antiviral activities.

Key words:

有效控制植物病害对于促进农业发展极其重要。当前，用于防治植物病害的主要方法依旧是化学防治，但是因其对环境污染、对人畜毒性较高以及农药残留等缺点，使其发展受到了极大的限制^[1-2]。同时，天然产物及仿生农药因具有对环境友好，作用位点独特以及高选择性的特点，在防治植物病害方面起着越来越重要的作用^[3]。姜黄素，作为一种来源于姜黄中的一种多酚类化合物，被广泛用作香料、食品防腐剂、味精以及染料^[4]。1, 4-戊二烯-3-酮类化合物是在姜黄素的结构基础上进行适当精简的, 依旧保持有抗病毒^[5]、抑菌^[6]、抗癌^[7]、抗炎^[8]、杀虫^[9]、抗氧化^[10]等广谱生物活性的一类衍生物。另一方面，肟酯类化合物因具有杀虫^[11]、抑菌^[12]、抗癌^[13]、抗痉挛^[14]、抗病毒^[15]、抗氧化^[16]等广泛的生理和药理活性，在医药和农药的创制中发挥着重要的作用。例如，2008年Liu等^[12]报道了系列含二氢吡唑单元的肟酯类化合物，生物活性测试结果表明，部分目标化合物对金黄色葡萄球菌和大肠杆菌表现出较强的抑制活性。同年Ouyang等^[15]报道了系列含吡唑结构的肟酯类化合物，生物活性测试结果表明，部分目标化合物对烟草花叶病毒表现出较强的抑制活性。2010年Sun等^[11]报道了系列含苯甲酰胺单元的肟酯类化合物，生物活性测试结果表明，部分化合物对粘虫表现出较强的触杀活性。为寻找低毒高效的绿色农药先导化合物, 设计合成了一系列含杂环的戊二烯酮肟酯类的化合物，并对其进行了初步的抑菌和抗病毒活性测试。生物测试结果表明，在测试浓度下，该类化合物具有一定的抑菌和抗病毒活性。目标化合物的合成路线如Scheme 1所示。

Figure Scheme 1. Synthesis of title compounds 5a~5f

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1 实验部分

1.1 仪器和试剂

JEOL-ECX500型500 MHz核磁共振仪 (日本电子株式会社)；LC-MS 1100/MSD型液质联用仪 (美国Agilent公司)；Prestige-21型红外光谱仪 (日本岛津公司)；X-4型数字显微熔点测定仪 (北京泰克仪器有限公司)，温度未校正；IKA RV10基本型旋转蒸发仪 (广州仪科实验技术有限公司)；IKA RCT基本型磁力搅拌器 (广州仪科实验技术有限公司)；BP61S型电子天平 (德国SartoriusBasic公司)；QY-20型三用紫外分析仪 (上海市安亭电子仪器厂)。

200~300 μm柱层层析硅胶 (青岛海洋化工分厂)；GF254薄层层析硅胶 (青岛海洋化工有限公司)；所用试剂均为分析纯。

1.2 实验方法

1.3 生物活性测试

1.2.1 中间体的合成

中间体1a和1b的制备采用文献[9]的合成方法；中间体2a~2d和3a~3f的制备采用文献[7]的合成方法；中间体4a~4f的制备采用文献[5]的合成方法。

Figure Scheme 2. Structures of the intermediates 1a, 1b, 2a~2d, 3a~3f

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表 1 中间体1a、1b、2a~2d和3a~3f的性状、产率及熔点 Table 1. Appearances, yields and melting points of intermediates 1a, 1b, 2a~2d, 3a~3f

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Compd.-O-R₁R₂FormulaAppearanceYield/%mp/℃1a2-O-yl--C₁₀H₁₀O₂Yellow solid87134~1363f2-O-ylFuran-2-yl4-NO₂-PhC₂₂H₁₇NO₅Yellow solid84156~157

1b	4-O-yl	-	-	C₁₀H₁₀O₂	Yellow solid	84	110~112
2a	2-O-yl	Furan-2-yl	-	C₁₅H₁₂O₃	Yellow solid	70	164~166
2b	4-O-yl	Furan-2-yl	-	C₁₅H₁₂O₃	Yellow solid	69	162~163
2c	2-O-yl	Thiophene-2-yl	-	C₁₅H₁₂O₂S	Yellow solid	72	153~155
2d	4-O-yl	Thiophene-2-yl	-	C₁₅H₁₂O₂S	Yellow solid	68	207~209
3a	4-O-yl	Furan-2-yl	Ph	C₂₂H₁₈O₃	Yellow solid	86	100~101
3b	4-O-yl	Furan-2-yl	3-F-Ph	C₂₂H₁₇FO₃	Yellow solid	73	118~119
3c	4-O-yl	Thiophene-2-yl	Ph	C₂₂H₁₈O₂S	Yellow solid	70	131~132
3d	4-O-yl	Thiophene-2-yl	2-Cl-Ph	C₂₂H₁₇ClO₂S	Yellow solid	95	85~87
3e	2-O-yl	Thiophene-2-yl	4-NO₂-Ph	C₂₂H₁₇NO₄S	Yellow solid	47	137~138

表 1 中间体1a、1b、2a~2d和3a~3f的性状、产率及熔点
Table 1. Appearances, yields and melting points of intermediates 1a, 1b, 2a~2d, 3a~3f

1-[4-(苄氧基) 苯基]-5-呋喃基-1, 4-戊二烯-3-酮肟 (4a)：白色固体, 产率71%, mp 128~129 ℃; IR (KBr), σ/cm^-1:3410, 3000, 2850, 1600, 1490, 1240, 965, 750；¹H NMR (500 MHz, CD₃COCD₃), δ:10.47(s, 1H, N—OH), 7.63(d, J=14.35 Hz, 1H, ArCH), 7.58(d, J=4.05 Hz, Furan—H), 7.54(d, J=8.6 Hz, 1H, ArH), 7.49(s, 2H, ArH), 7.40(t, 2H, ArH), 7.33(t, 2H, ArH), 7.20~6.98(m, 3H, ArH, FuranCH, ArCCH), 6.84(t, 1H, Furan—H), 6.63(s, 1H, Furan—H), 6.51(d, J=15.45 Hz, 1H, FuranCCH), 5.16(s, 2H, CH₂); ¹³C NMR (125 MHz, CD₃COCD₃), δ:166.81, 164.52, 136.55, 135.21, 133.21, 132.71, 132.63, 130.25, 128.11, 127.78, 127.26, 127.05, 126.47, 126.28, 125.71, 121.99, 121.32, 116.85, 111.73, 69.91。

1-[4-(3-氟苄氧基) 苯基]-5-呋喃基-1, 4-戊二烯-3-酮肟 (4b)：白色固体, 产率78%, mp 121~122 ℃; IR (KBr), σ/cm^-1:3400, 3230, 3000, 1605, 1510, 1226, 965, 748;¹H NMR (500 MHz, CD₃COCD₃), δ:10.54(s, 1H, N—OH), 7.64~7.55(m, 3H, ArH), 7.45(d, J=5.15 Hz, 1H, Furan—H), 7.34~6.99(m, 8H, ArH, ArCH, FuranCH, ArCCH), 6.86(t, 1H, Furan—H), 6.64(s, 1H, Furan—H), 6.52(d, J=16.60 Hz, 1H, FuranCCH), 5.19(s, 2H, CH₂); ¹³C NMR (125 MHz, CD₃COCD₃), δ:163.91, 158.82, 152.90, 143.79, 143.04, 135.30, 132.35, 130.45, 130.39, 128.71, 128.31, 123.30, 123.23, 121.04, 120.50, 112.08, 111.89, 111.77, 110.15, 68.78.

1-[4-(苄氧基) 苯基]-5-噻吩基-1, 4-戊二烯-3-酮肟 (4c)：白色固体, 产率80%, mp 148~149 ℃; IR (KBr), σ/cm^-1:3150, 3147, 3010, 1598, 1518, 1235, 970, 750;¹H NMR (500 MHz, CD₃COCD₃), δ:10.59(s, 1H, N—OH), 7.59(d, J=8.55 Hz, 1H, ArH), 7.54(d, J=8.6 Hz, 1H, ArH), 7.46(t, 3H, ArH, Thiophene—H), 7.39(t, 2H, ArH), 7.34~7.29(m, 3H, ArH, ArCH), 7.25~7.01(m, 4H, ArH, Thiophene—H), 6.89(d, J=16.00 Hz, 1H, ArCCH), 6.78(d, J=16.00 Hz, 1H, ThiopheneCCH), 5.15(s, 2H, CH₂); ¹³C NMR (125 MHz, CD₃COCD₃), δ:159.63, 159.14, 152.98, 152.74, 142.22, 135.60, 132.61, 129.61, 128.73, 128.53, 128.34, 127.90, 127.67, 126.54, 126.05, 125.49, 122.40, 120.75, 116.18, 115.20, 114.81, 69.69。

1-[4-(2-氯苄氧基) 苯基]-5-噻吩基-1, 4-戊二烯-3-酮肟 (4d)：白色固体, 产率66%, mp 158~160 ℃; IR (KBr), σ/cm^-1:3151, 3133, 3015, 1600, 1520, 1260, 978, 745;¹H NMR (500 MHz, CD₃COCD₃), δ:10.54(s, 1H, N—OH), 7.63(d, J=7.4 Hz, 2H, ArH), 7.58(d, J=8.60 Hz, 1H, ArH), 7.47(d, J=16.05 Hz, 2H, ArCH, ThiopheneCCH), 7.39~7.20(m, 4H, ArH, Thiophene—H), 7.15~7.05(m, 3H, ArH, Thiophene—H), 6.90(d, J=16.05 Hz, 1H, ArCCH), 6.77(d, J=16.05 Hz, 1H, ThiopheneCCH), 5.24(s, 2H, CH₂); ¹³C NMR (125 MHz, CD₃COCD₃), δ:159.36, 158.87, 142.21, 135.47, 132.46, 129.66, 129.45, 128.91, 128.83, 128.76, 128.37, 128.03, 127.86, 127.54, 127.30, 126.50, 125.99, 125.46, 122.39, 120.47, 116.15, 67.09。

1-[2-(4-硝基苄氧基) 苯基]-5-噻吩基-1, 4-戊二烯-3-酮肟 (4e)：白色固体, 产率77%, mp 91~92 ℃; IR (KBr), σ/cm^-1:3152, 3090, 3023, 1609, 1543, 1261, 981, 743;¹H NMR (500 MHz, CD₃COCD₃), δ:8.10(d, J=8.00 Hz, 2H, ArH), 7.59(d, J=17.75 Hz, 1H, ArCH), 7.56~7.48(m, 2H, ArH, Thiophene—H), 7.43~7.42(m, 1H, ArH), 7.38~7.25(m, 3H, ArH, ThiopheneCCH), 7.21(t, 1H, Thiophene—H), 7.17~7.12(m, 1H, ThiopheneCCH), 7.10~6.98(m, 2H, Thiophene—H, ArCCH), 6.75(d, J=16.00 Hz, 1H, ThiopheneCCH), 5.19(s, 2H, CH₂); ¹³C NMR (125 MHz, CD₃COCD₃), δ:161.75, 160.49, 152.41, 152.05, 142.15, 130.84, 130.15, 129.47, 128.90, 128.57, 127.90, 127.62, 127.40, 126.96, 126.30, 125.48, 122.54, 121.04, 117.21, 116.18, 112.75, 69.89。

1-[2-(4-硝基苄氧基) 苯基]-5-呋喃基-1, 4-戊二烯-3-酮肟 (4f)：白色固体, 产率57%, mp 165~167 ℃; IR (KBr), σ/cm^-1:3151, 3100, 3015, 1615, 1543, 1265, 985, 748;¹H NMR (500 MHz, CD₃COCD₃), δ:10.78(s, 1H, N—OH), 8.18(d, J=7.55 Hz, 2H, ArH), 7.89(s, 1H, Furan—H), 7.59~7.55(m, 1H, ArCH), 7.53(t, 2H, ArH), 7.45(d, J=17.20 Hz, 1H, FuranCH), 7.37~7.27(m, 4H, ArH, ArCCH), 7.14(t, 1H, Furan—H), 7.06~6.98(m, 1H, Furan—H), 6.82(d, J=16.60 Hz, 1H, FuranCCH), 5.18(s, 2H, CH₂); ¹³C NMR (125 MHz, CD₃COCD₃), δ:163.71, 162.12, 152.01, 151.02, 130.73, 130.10, 129.42, 128.55, 127.81, 127.38, 127.03, 123.18, 122.79, 121.26, 120.72, 117.33, 114.85, 112.98, 111.89, 110.19, 69.87。

1.2.2 目标化合物的合成

目标化合物5a~5f通过采用文献[13]的合成方法加以改进制得：在25 mL的三口瓶中，依次加入中间体4(1 mmol)，三乙胺 (0.12 g，1.17 mmol)，5 mL氯仿，冰浴条件下搅拌，待温度降至3 ℃左右时缓慢滴加芳酰氯 (1.1 mmol)，并控制温度在0~5 ℃下搅拌反应3 h后常温搅拌，TLC跟踪反应，反应18 h后原料点消失，得到黄色澄清溶液。10%(质量分数) NaHCO₃溶液洗涤 (25 mL×4)，水洗 (25 mL×4)，无水硫酸镁干燥，过滤、旋蒸除去二氯甲烷，得到黄色粘稠状液体。柱层析分离得到目标化合物5a~5f。

苯甲酸-1-[4-(苄氧基) 苯基]-5-呋喃基-1, 4-戊二烯-3-酮肟酯 (5a):棕色固体, 产率50%, mp 143~144 ℃; IR (KBr), σ/cm^-1:3100, 3050, 1750, 1634, 1599, 1518, 1238, 1171, 1088, 1065, 1012, 914, 824, 743, 714;¹H NMR (500 MHz, CD₃COCD₃), δ:8.16(d, J=8.40 Hz, 2H, ArH), 7.70(d, J=9.20 Hz, 2H, ArH), 7.68~7.67(m, 1H, ArH), 7.56(t, 2H, ArH), 7.48(d, J=6.80 Hz, 2H, ArH), 7.40~7.38(m, 3H, ArH), 7.34(d, J=4.50 Hz, 1H, Furan—H), 7.30(d, J=16.00 Hz, 1H, ArCH), 7.07(d, J=8.50 Hz, 2H, ArH), 6.96(d, J=16.00 Hz, 1H, FuranCCH), 6.73(d, J=3.50 Hz, 1H, Furan—H), 6.56~6.54(m, 1H, Furan—H), 5.16(s, 2H, CH₂); ¹³C NMR (125 MHz, CD₃COCD₃), δ:163.00, 160.63, 160.42, 152.19, 144.22, 139.93, 137.18, 133.45, 129.60, 129.47, 129.44, 129.53, 128.90, 128.60, 128.56, 127.97, 127.68, 125.04, 118.17, 115.34, 114.31, 112.66, 112.29, 69.76;HRMS (ESI) 计算值C₂₉H₂₃NO₄[M+Na]⁺:472.1627, 实测值: 472.1558。

4-氯苯甲酸-1-[4-(3-氟苄氧基) 苯基]-5-呋喃基-1, 4-戊二烯-3-酮肟酯 (5b):白色固体, 产率48%, mp 162~164 ℃; IR (KBr), σ/cm^-1:3080, 3060, 2940, 2910, 1734, 1593, 1558, 1515, 1248, 1173, 1076, 1013, 748;¹H NMR (500 MHz, CD₃COCD₃), δ:8.15~8.11(m, 2H, ArH), 7.72(d, J=8.00 Hz, 2H, ArH), 7.67~7.58(m, 3H, ArH, Furan—H), 7.46~7.38(m, 3H, ArH), 7.34~7.30(m, 2H, ArH), 7.26(d, J=8.05 Hz, 1H, ArH), 7.07(t, 2H, Furan—H), 7.02(d, J=16.60 Hz, 1H, FuranCH), 6.94(d, J=16.05 Hz, 1H, ArCH), 6.73(s, 1H, FuranCCH), 6.58(d, J=16.60 Hz, 1H, ArCCH), 5.20(s, 2H, CH₂); ¹³C NMR (125 MHz, CD₃COCD₃), δ:163.91, 162.22, 160.15, 159.63, 152.14, 145.08, 144.25, 140.04, 139.21, 139.17, 137.66, 131.25, 131.14, 130.48, 130.42, 129.66, 129.20, 129.11, 127.48, 125.17, 123.25, 117.97, 117.63, 115.35, 115.21, 114.33, 112.72, 68.85;HRMS (ESI) 计算值C₂₉H₂₁ClFNO₄[M+Na]⁺:524.1143, 实测值:524.1076。

4-氯苯甲酸-1-[4-(苄氧基) 苯基]-5-噻吩基-1, 4-戊二烯-3-酮肟酯 (5c):白色固体, 产率54%, mp 193~194 ℃; IR (KBr), σ/cm^-1:3070, 3030, 2970, 2930, 1734, 1593, 1553, 1525, 1248, 1173, 1076, 1023, 748;¹H NMR (500 MHz, CD₃COCD₃), δ:8.13(t, 2H, ArH), 7.70(d, J=8.60 Hz, 1H, ArH), 7.65~7.59(m, 3H, ArH), 7.53(d, J=5.15 Hz, 1H, Thiophene—H), 7.48(d, J=7.40 Hz, 1H, ArH), 7.42~7.39(m, 4H, ArH), 7.35~7.32(m, 1H, ArH), 7.26(d, J=16.00 Hz, 1H, ThiopheneCCH), 7.14~7.02(m, 3H, ArH, Thiophene—H), 6.91(d, J=15.45 Hz, 1H, ArCH), 5.18(s, 2H, CH₂); ¹³C NMR (125 MHz, CD₃COCD₃), δ:161.01, 160.45, 159.96, 141.18, 140.28, 139.17, 137.82, 137.28, 137.18, 133.36, 131.26, 131.14, 131.03, 130.61, 129.63, 129.50, 129.20, 129.17, 129.12, 128.56, 128.15, 127.96, 127.93. 127.66. 127.30. 115.34, 115.21, 69.71;HRMS (ESI) 计算值C₂₉H₂₂ClNO₃S[M+Na]⁺:522.1009, 实测值:522.1060。

4-氯苯甲酸-1-[4-(2-氯苄氧基) 苯基]-5-噻吩基-1, 4-戊二烯-3-酮肟酯 (5d):黄色针状晶体, 产率44%, mp 138~139 ℃; IR (KBr), σ/cm^-1:3120, 3050, 2900, 2850, 1742, 1601, 1506, 1248, 1173, 1067, 1013, 961, 914, 822, 748, 700;¹H NMR (500 MHz, CD₃COCD₃), δ:8.21~8.16(m, 2H, ArH), 7.78(d, J=8.60 Hz, 1H, ArH), 7.73~7.62(m, 5H, ArH), 7.57(d, J=5.15 Hz, 1H, Thiophene—H), 7.55~7.51(m, 1H, ArH), 7.45~7.43(m, 3H, ArH), 7.30(d, J=16.60 Hz, 1H, ThiopheneCCH), 7.17~7.11(m, 3H, Thiophene—H, ArCH), 7.07(d, J=16.05 Hz, 1H, ThiopheneCCH), 6.95(d, J=16.05 Hz, 1H, ArCCH), 5.28(s, 2H, CH₂); ¹³C NMR (125 MHz, CD₃COCD₃), δ:162.22, 160.12, 159.60, 141.20, 140.09, 139.18, 137.71, 134.63, 134.53, 133.31, 132.83, 131.25, 131.13, 131.01, 130.64, 129.71, 129.61, 129.47, 129.26, 129.13, 129.10, 128.43, 128.15, 127.33, 127.27, 115.26, 115.12, 67.16;HRMS (ESI) 计算值C₂₉H₂₁Cl₂NO₃S[M+Na]⁺:556.0619, 实测值:556.0590。

4-氯苯甲酸-1-[2-(4-硝基苄氧基) 苯基]-5-噻吩基-1, 4-戊二烯-3-酮肟酯 (5e):白色固体, 产率32%, mp 183~185 ℃; IR (KBr), σ/cm^-1:2950, 2900, 2850, 1748, 1520, 1456, 1346, 1261, 1092, 1030, 800, 739;¹H NMR (500 MHz, CD₃COCD₃), δ:8.33(d, J=8.60 Hz, 2H, ArH), 8.13(d, J=16.05 Hz, 1H, ArCH), 8.04(d, J=8.60 Hz, 2H, ArH), 7.89(d, J=16.60 Hz, 1H, ThiopheneCH), 7.85~7.78(m, 2H, ArH), 7.66~7.63(m, 1H, Thiophene—H), 7.55(d, J=8.55 Hz, 1H, ArH), 7.50(d, J=3.40 Hz, 2H, Thiophene—H), 7.35(d, J=16.00 Hz, 1H, ThiopheneCH), 7.20~7.15(m, 2H, ArH), 7.10~7.05(m, 1H, ArH), 6.93(d, J=15.54 Hz, 1H, ArCCH), 5.46(s, 2H, CH₂); ¹³C NMR (125 MHz, CD₃COCD₃), δ:162.07, 161.39, 156.88, 152.09, 149.49, 145.14, 144.37, 139.12, 135.60, 132.99, 131.30, 131.17, 131.12, 130.69, 129.19, 129.05, 128.69, 128.24, 128.03, 127.75, 127.49, 125.62, 123.70, 123.59, 121.63, 118.20, 113.93, 112.32, 69.03;HRMS (ESI) 计算值C₂₉H₂₁ClN₂O₅S[M+Na]⁺:567.0860, 实测值:567.0830。

2-氟苯甲酸-1-[2-(4-硝基苄氧基) 苯基]-5-呋喃基-1, 4-戊二烯-3-酮肟酯 (5f):黄色固体, 产率38%, mp 180~181 ℃; IR (KBr), σ/cm^-1:2963, 2900, 2850, 1734, 1717, 1601, 1520, 1489, 1456, 1346, 1285, 1260, 1233, 1107, 1084, 1030, 802, 737;¹H NMR (500 MHz, CD₃COCD₃), δ:8.26(d, J=8.60 Hz, 1H, ArH), 8.18(d, J=8.60 Hz, 1H, ArH), 8.09~8.02(m, 1H, ArH), 7.89(d, J=16.60 Hz, 1H, ArCH), 7.86~7.01(m, 5H, ArH, Furan—H), 7.64(d, J=16.60 Hz, 1H, FuranCH), 7.44~7.14(m, 7H, ArH, Furan—H, FuranCCH), 6.97(d, J=16.05 Hz, 1H, ArCCH), 6.75(t, 1H, Furan—H), 5.44(s, 2H, CH₂); ¹³C NMR (125 MHz, CD₃COCD₃), δ:164.21, 163.62, 160.75, 157.66, 151.55, 146.81, 143.75, 142.88, 135.51, 135.21, 133.89, 131.43, 130.91, 130.71, 128.99, 128.81, 128.71, 128.01, 125.67, 124.91, 124.15, 124.14, 120.98, 118.77, 115.41, 114.21, 113.87, 112.77, 69.85;HRMS (ESI) 计算值C₂₉H₂₁FN₂O₆[M+Na]⁺:535.1384, 实测值:535.1417。

1.3.2 目标化合物的抗病毒活性测试

采用半叶枯斑法^[5]，在药剂浓度为500 mg/L时，以龄期一致的新叶烟为测试对象，对目标化合物5a~5f进行了抗烟草花叶病毒 (TMV) 活性的测验，以商品药剂宁南霉素为对照药剂。

1.3.1 目标化合物的抑菌生物活性测试

采用生长速率法^[17]，在药剂浓度为50 mg/L时，以小麦赤霉病菌 (G.zeae)、水稻纹枯病菌 (F.oxysporum) 和苹果腐烂病菌 (C.mandshurica) 为供试菌株，对目标化合物5a~5f进行了抑菌活性的测定，以商品药剂氟环唑为对照药剂。

2 结果与讨论

2.1 目标化合物的合成

以目标化合物5a的合成为例，探讨了不同溶剂、温度、时间和碱对其收率的影响。当分别选用乙腈、二氯甲烷和氯仿为溶剂，碳酸钾、三乙胺和吡啶为碱合成化合物5a时，在常温反应18 h后，均有目标化合物生成，其中当溶剂为二氯甲烷，三乙胺为碱时，化合物5a的收率最高，为50%。当选用二氯甲烷为溶剂，三乙胺为碱时，分别在常温条件下反应3、6、12、18及24 h后，发现当反应时间为18 h后，化合物5a的收率最高，为50%。当选用二氯甲烷为溶剂，三乙胺为碱，在温度为5、15、20、25及30 ℃下反应18 h后，发现当温度为20 ℃时，化合物5a的收率最高，为50%。因此，当选用二氯甲烷为溶剂，三乙胺为碱，在室温下反应18 h，能很好的制备目标化合物。

2.2 目标化合物的图谱解析

在IR谱图中，在1750 cm^-1处出现1个强尖吸收峰为肟酯的CO伸缩振动吸收，可与其它羰基化合物相区别；在1634 cm^-1附近的吸收峰为NC伸缩振动的吸收；在1238 cm^-1处出现的第一吸收峰为C—O—N非对称伸缩振动的吸收；在1171 cm^-1处出现的一个强尖峰是由C—O—C键反对称伸缩振动引起的。在¹H NMR谱图中，苯环上的质子和烯烃的质子的化学位移出现在δ 8.20~6.50处，苄基上亚甲基上的氢的化学位移出现在δ 5.16处。在HRMS (ESI) 谱图中，目标化合物均出现有[M+Na]⁺的峰。

2.3 目标化合物的抑菌活性

按1.3.1节生物活性测试方法，在药剂浓度为50 mg/L时，以小麦赤霉病菌 (G.zeae)、水稻纹枯病菌 (F.oxysporum) 和苹果腐烂病菌 (C.mandshurica) 为供试菌株，对目标化合物5a~5f进行了抑菌活性的测定，其结果如表 2所示。

表 2 目标化合物5a~5f的抑菌活性 (50 mg/L) Table 2. Fungicidal activities of the title compounds 5a~5f at 50 mg/L

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Compd.G.zeae/%F.oxysporum/%C.mandshurica/% 5a9.15±2.9318.49±0.6316.25±1.87Epoxiconazole100±6.05100±6.48100±5.91

5b	33.56±1.36	58.56±0.87	46.57±1.06
5c	3.44±1.11	1.45±0.85	9.35±1.39
5d	64.75±1.33	52.05±2.30	69.68±0.70
5e	48.14±11.72	56.51±0.84	66.06±1.04
5f	26.44±0.52	55.48±1.44	41.52±1.08

表 2 目标化合物5a~5f的抑菌活性 (50 mg/L)
Table 2. Fungicidal activities of the title compounds 5a~5f at 50 mg/L

由表 2可以看出，在药剂浓度为50 mg/L时，该系列化合物具有一定的抑菌活性。其中化合物5d对小麦赤霉病菌的抑制作用最好为64.75%，化合物5b、5d、5e和5f对水稻纹枯病菌有良好的抑制活性，其抑制率分别为58.56%、52.05%、56.51%和55.48%, 化合物5d和5e对苹果腐烂病菌有良好的抑制活性，其抑制率分别为69.68%和66.06%。

2.4 目标化合物的抗病毒活性

按1.3.2节生物活性测试方法，在药剂浓度为500 mg/L时，以龄期一致的新叶烟为测试对象，对目标化合物5a~5f进行了抗烟草花叶病毒 (TMV) 活性的测验，其结果如表 3所示。

表 3 标化合物5a~5f的抗病毒活性 (500 mg/L) Table 3. Antiviral activities of compounds 5a~5f at 500 mg/L

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Compd5a5b5c5d5e5fNinanmycinCurative/%39.6733.9536.6856.9353.0853.4064.62Inactivitation/%75.0970.8166.8386.8983.5189.0197.27

表 3 标化合物5a~5f的抗病毒活性 (500 mg/L)
Table 3. Antiviral activities of compounds 5a~5f at 500 mg/L

由表 3可以看出，在药剂浓度为500 mg/L时，该系列化合物具有一定的抗TMV活性。其中化合物5d、5e和5f对TMV的抑制作用相对较好，其治疗活性分别为56.93%、53.08%和53.40%, 略低于其对照药剂宁南霉素 (64.62%), 其钝化活性分别为86.89%、83.51%和89.01%，略低于其对照药剂宁南霉素 (97.27%)。

3 结论

以姜黄素为先导，采用活性基团拼接原理，设计合成了6个含杂环1, 4-戊二烯-3-酮肟酯类化合物，其结构经IR、¹H NMR、¹³C NMR和HRMS确认。采用生长速率法，在药剂浓度为50 mg/L时，以小麦赤霉病菌、水稻纹枯病菌和苹果腐烂病菌为供试菌株，对目标化合物进行了抑菌活性的测定，结果表明，部分目标化合物对以上菌种具有一定的抑制活性。采用半叶枯斑法，在药剂浓度为500 mg/L时，以龄期一致的新叶烟为测试对象，对目标化合物5a~5f进行了抗烟草花叶病毒活性的测验, 结果表明，部分目标化合物对烟草花叶病毒具有较好的抑制活性。这也表明在1, 4-戊二烯-3-酮肟酯类化合物的基础上进行结构修饰，有望得到具有较高生物活性的有机化合物分子。

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Scheme 1 Synthesis of title compounds 5a~5f

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Scheme 2 Structures of the intermediates 1a, 1b, 2a~2d, 3a~3f

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表 1 中间体1a、1b、2a~2d和3a~3f的性状、产率及熔点

Table 1. Appearances, yields and melting points of intermediates 1a, 1b, 2a~2d, 3a~3f

Compd.-O-R₁R₂FormulaAppearanceYield/%mp/℃1a2-O-yl--C₁₀H₁₀O₂Yellow solid87134~1363f2-O-ylFuran-2-yl4-NO₂-PhC₂₂H₁₇NO₅Yellow solid84156~157

1b	4-O-yl	-	-	C₁₀H₁₀O₂	Yellow solid	84	110~112
2a	2-O-yl	Furan-2-yl	-	C₁₅H₁₂O₃	Yellow solid	70	164~166
2b	4-O-yl	Furan-2-yl	-	C₁₅H₁₂O₃	Yellow solid	69	162~163
2c	2-O-yl	Thiophene-2-yl	-	C₁₅H₁₂O₂S	Yellow solid	72	153~155
2d	4-O-yl	Thiophene-2-yl	-	C₁₅H₁₂O₂S	Yellow solid	68	207~209
3a	4-O-yl	Furan-2-yl	Ph	C₂₂H₁₈O₃	Yellow solid	86	100~101
3b	4-O-yl	Furan-2-yl	3-F-Ph	C₂₂H₁₇FO₃	Yellow solid	73	118~119
3c	4-O-yl	Thiophene-2-yl	Ph	C₂₂H₁₈O₂S	Yellow solid	70	131~132
3d	4-O-yl	Thiophene-2-yl	2-Cl-Ph	C₂₂H₁₇ClO₂S	Yellow solid	95	85~87
3e	2-O-yl	Thiophene-2-yl	4-NO₂-Ph	C₂₂H₁₇NO₄S	Yellow solid	47	137~138

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表 2 目标化合物5a~5f的抑菌活性 (50 mg/L)

Table 2. Fungicidal activities of the title compounds 5a~5f at 50 mg/L

Compd.G.zeae/%F.oxysporum/%C.mandshurica/% 5a9.15±2.9318.49±0.6316.25±1.87Epoxiconazole100±6.05100±6.48100±5.91

5b	33.56±1.36	58.56±0.87	46.57±1.06
5c	3.44±1.11	1.45±0.85	9.35±1.39
5d	64.75±1.33	52.05±2.30	69.68±0.70
5e	48.14±11.72	56.51±0.84	66.06±1.04
5f	26.44±0.52	55.48±1.44	41.52±1.08

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表 3 标化合物5a~5f的抗病毒活性 (500 mg/L)

Table 3. Antiviral activities of compounds 5a~5f at 500 mg/L

Compd5a5b5c5d5e5fNinanmycinCurative/%39.6733.9536.6856.9353.0853.4064.62Inactivitation/%75.0970.8166.8386.8983.5189.0197.27

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沈阳化工大学材料科学与工程学院沈阳 110142