CN107950537B - 咪唑类生物碱在治疗植物病毒和病菌中的应用 - Google Patents
咪唑类生物碱在治疗植物病毒和病菌中的应用 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
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Abstract
本发明公开了一种Naamine及Naamidine类生物碱在治疗植物病毒和病菌中的应用，本发明首次发现Naamine及Naamidine类生物碱I‑1～I‑8表现出很好的抗植物病毒和病菌活性，能很好地抑制烟草花叶病毒和黄瓜枯萎，花生褐斑，苹果轮纹，小麦纹枯，玉米小斑，西瓜炭疽，水稻恶苗，番茄早疫，小麦赤霉，马铃薯晚疫，辣椒疫霉，油菜菌核，黄瓜灰霉和水稻纹枯14种植物病菌。
Description
技术领域
本发明属于农业防护技术领域，具体来说涉及一种咪唑类生物碱在治疗植物病毒和病菌中的应用。
背景技术
海洋是人类物质资源的天然宝库，已知海洋生物的物种总数占地球生物的80％以上(J Antibiot(Tokyo),1994,47,1425–1433)，目前从海绵、海兔、海鞘、海藻、鲨鱼、珊瑚等海洋生物中分离获得7000余种海洋天然产物，新发现的化合物还在以加速度递增。在已发现的化合物中包括萜类、多肽、甾体类、聚醚类、生物碱、大环内酯类、多糖等化合物，约50％具有各种生物活性，超过0.1％的化合物结构新颖，活性显著，极有可能开发成药(Chem.Rev.2015,115,9655-9706)。因此，从海洋天然产物中寻找新型活性药物先导已成为当今研究的热点。
由于Naamine及Naamidine类生物碱天然含量较低，且合成较为困难，生物活性研究还不够深入，主要集中在抗癌活性方面，在抗人体病毒和病菌方面的研究还处于初级阶段，并且在抗植物病毒和病菌中的应用还没有报道，并且人体病毒病菌和植物病毒病菌有很大的区别，绝大多数情况下二者互不传染。
发明内容
针对现有技术的不足，本发明的目的是提供一种咪唑类生物碱在治疗植物病毒和病菌中的应用，该Naamine及Naamidine类生物碱具有很好的抗植物病毒和病菌活性。
本发明是通过下属技术方案予以实现的。
一种Naamine及Naamidine类生物碱在治疗植物病毒中的应用，所述Naamine及Naamidine类生物碱为下述I-1～I-8结构式中的一种：
在上述技术方案中，所述Naamine及Naamidine类生物碱的处理计量为100～500μg/mL。
在上述技术方案中，所述病毒为烟草花叶病毒。
一种Naamine及Naamidine类生物碱在治疗植物病菌中的应用，所述Naamine及Naamidine类生物碱为下述I-1～I-8结构式中的一种：
在上述技术方案中，所述植物病菌为黄瓜枯萎、花生褐癍、苹果轮纹、小麦纹枯、玉米小斑、西瓜炭疽、水稻恶苗、番茄早疫、小麦赤霉、马铃薯晚疫、辣椒疫霉、油菜菌核、黄瓜灰霉和水稻纹枯。
相比于现有技术，本发明首次发现Naamine及Naamidine类生物碱I-1～I-8表现出很好的抗植物病毒和病菌活性，能很好地抑制烟草花叶病毒(TMV)和黄瓜枯萎，花生褐斑，苹果轮纹，小麦纹枯，玉米小斑，西瓜炭疽，水稻恶苗，番茄早疫，小麦赤霉，马铃薯晚疫，辣椒疫霉，油菜菌核，黄瓜灰霉和水稻纹枯14种植物病菌。
具体实施方式
Naamine及Naamidine类生物碱为下述I-1～I-8结构式：
在本发明的实施例中，Naamine及Naamidine类生物碱的I-1～I-8结构式按照下述参考文献制备：J.Org.Chem.2015,80,10076-10085。测定熔点的仪器为X-4型显微熔点测定仪(购买自北京泰克仪器有限公司)；核磁共振波谱仪的型号为Bruker AV400，以TMS为内标，CDCl3、CD3OD或DMSO-d6作溶剂；高分辨质谱仪的型号为Varian 7.0T FTICR-MS；在本发明的实施例中，药品均购买自百灵威，试剂均购买于天津试剂六厂。
下面结合实施例对本发明的咪唑类生物碱在治疗植物病毒和病菌中的应用进行详细说明。
实施例1：Naamine及Naamidine类生物碱I-1～I-8结构式的实验数据
I-1：白色固体，Mp(熔点):120–123℃，1H NMR(400MHz,CDCl3)δ7.43–7.30(m,5H,Ar-H),7.16(d,J＝8.3Hz,2H,Ar-H),6.98(d,J＝8.3Hz,2H,Ar-H),6.87(d,J＝8.4Hz,2H,Ar-H),6.79(d,J＝8.4Hz,2H,Ar-H),5.03(s,2H,O-CH2),3.85(s,2H,NH2),3.81(s,2H,CH2),3.75(s,3H,O-CH3),3.74(s,2H,CH2),3.07(s,3H,N-CH3).
I-2：灰白色固体，Mp:202–205℃，1H NMR(400MHz,CD3OD)δ7.09(d,J＝8.6Hz,2H,Ar-H),6.85(d,J＝8.4Hz,2H,Ar-H),6.77(d,J＝8.6Hz,2H,Ar-H),6.65(d,J＝8.4Hz,2H,Ar-H),3.77(s,2H,CH2),3.73(s,3H,O-CH3),3.70(s,2H,CH2),3.09(s,3H,N-CH3).13C NMR(100MHz,CD3OD)δ160.0,157.5,148.4,131.5,130.5,130.2,129.0,125.2,123.8,116.6,115.1,55.7,30.2,29.8,28.5.HRMS(高分辨率质谱仪)(ESI)calcd for C19H22N3O2 +[M+H]+324.1707,found 324.1707.
I-3：黄色固体，Mp:186–190℃，1H NMR(400MHz,CDCl3)δ7.11(d,J＝8.5Hz,2H,Ar-H),6.85–6.79(m,4H,Ar-H),6.74(d,J＝8.4Hz,2H,Ar-H),3.88(s,2H,CH2),3.87(s,2H,CH2),3.77(s,3H,O-CH3),3.37(s,3H,N-CH3),3.17(s,3H,N-CH3).13C NMR(100MHz,CDCl3)δ163.5,158.3,157.7,155.2,148.5,146.4,133.7,130.9,129.3,129.0,128.1,126.8,115.8,114.1,55.3,31.7,29.7,28.6,24.8.HRMS(ESI)calcd for C23H24N5O4 +[M+H]+434.1823,found 434.1826.
I-4：灰白色固体，Mp:207–209℃，1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),9.28(s,1H),8.09(s,2H,Ar-H),7.43(s,3H,Ar-H),7.20(d,J＝7.6Hz,2H,Ar-H),6.91(d,J＝7.8Hz,2H,Ar-H),6.85(d,J＝7.7Hz,2H,Ar-H),6.68(d,J＝7.3Hz,2H,Ar-H),3.93(s,4H,CH2),3.71(s,3H,O-CH3),3.25(s,3H,N-CH3).13C NMR(100MHz,DMSO-d6)δ157.7,155.9,131.4,130.6,129.4,129.0,128.4,128.2,127.8,127.6,115.4,113.8,55.0,28.9,27.2.HRMS(ESI)calcd for C26H26N3O3 +[M+H]+428.1969,found 428.1971.
I-5：砖红色固体，熔点163–165℃，1H NMR(400MHz,CD3OD)δ7.14(d,J＝8.5Hz,2H,Ar-H),6.77(d,J＝8.5Hz,2H,Ar-H),6.66(d,J＝8.0Hz,1H,Ar-H),6.53(dd,J＝8.0,1.4Hz,1H,Ar-H),6.45(d,J＝1.4Hz,1H,Ar-H),3.80(s,2H,CH2),3.73(s,3H,O-CH3),3.72(s,2H,CH2),3.58(s,3H,O-CH3),3.09(s,3H,N-CH3).13C NMR(100MHz,CD3OD)δ159.4,149.7,149.2,146.1,134.7,132.7,131.8,130.5,122.6,121.6,116.1,114.7,112.6,56.2,55.7,32.8,29.7,29.5.HRMS(ESI)calcd for C20H24N3O3 +[M+H]+354.1812,found 354.1818.
I-6：黄色固体，熔点157–159℃，1H NMR(400MHz,CDCl3)δ7.12(d,J＝8.5Hz,2H,Ar-H),6.82(d,J＝8.5Hz,2H,Ar-H),6.72(d,J＝8.1Hz,1H,Ar-H),6.58(s,1H,Ar-H),6.46(d,J＝8.1Hz,1H,Ar-H),3.89(s,2H,CH2),3.86(s,5H,CH2 and O-CH3),3.78(s,3H,O-CH3),3.49(s,3H,N-CH3),3.17(s,3H,N-CH3).13C NMR(100MHz,CDCl3)δ162.4,158.2,155.8,146.4,145.9,145.4,145.2,135.5,131.4,130.2,129.3,126.7,119.2,114.2,114.0,110.8,56.0,55.3,32.2,29.9,28.8,24.7.HRMS(ESI)calcd for C24H26N5O5 +[M+H]+464.1928,found464.1934.
I-7：砖红色固体，熔点172–174℃，1H NMR(400MHz,CD3OD)δ7.05(d,J＝8.3Hz,2H,Ar-H),6.67(d,J＝8.3Hz,2H,Ar-H),6.16(s,2H,Ar-H),3.71(s,2H,CH2),3.62(s,5H,CH2and O-CH3),3.54(s,6H,O-CH3),3.01(s,3H,N-CH3).13C NMR(100MHz,CD3OD)δ159.4,149.7,149.3,134.9,134.7,132.8,131.1,130.5,122.4,114.7,106.2,56.6,55.7,32.8,30.1,29.5.HRMS(ESI)calcd for C21H26N3O4 +[M+H]+384.1918,found 384.1919.
I-8：棕色固体，熔点144–146℃，1H NMR(400MHz,CDCl3)δ7.15(d,J＝7.9Hz,2H,Ar-H),6.80(d,J＝7.9Hz,2H,Ar-H),6.15(s,2H,Ar-H),3.91(s,2H,CH2),3.89(s,2H,CH2),3.76(s,3H,O-CH3),3.70(s,6H,O-CH3),3.50(s,3H,N-CH3),3.18(s,3H,N-CH3).13C NMR(101MHz,CDCl3)δ162.1,158.2,155.2,147.2,146.5,144.2,136.2,133.5,131.7,129.3,128.1,126.7,114.0,104.6,56.2,55.3,32.2,30.0,29.7,24.7.HRMS(ESI)calcd for C25H28N5O6 +[M+H]+494.2034,found 494.2030.
实施例2：抗烟草花叶病毒活性的测定，测定程序如下：
1、病毒提纯及浓度测定：
病毒提纯及浓度测定参照南开大学元素所生测室编制烟草花叶病毒SOP规范执行。病毒粗提液经2次聚乙二醇离心处理后，测定浓度，4℃冷藏备用。
2、化合物溶液配制：
称量后，原药(I-1～I-8结构式中的一种)加入DMF(二甲基甲酰胺)溶解，制得1×105μg/mL母液，后用含1wt‰吐温80水溶液稀释至所需浓度；宁南霉素制剂直接兑水稀释。
3、离体作用：
摩擦接种珊西烟适龄叶片，用流水冲洗，病毒浓度10μg/mL。收干后剪下，沿叶中脉对剖，左右半叶分别浸于1‰wt吐温水及药剂中，30min后取出，于适宜光照温度下保湿培养，每3片叶为1次重复，重复3次。3d后记录病斑数，计算防效。
4、活体保护作用：
选长势均匀一致的3–5叶期珊西烟，全株喷雾施药，每处理3次重复，并设1wt‰吐温80水溶液对照。24h后，叶面撒布金刚砂(500目)，用毛笔蘸取病毒液，在全叶面沿支脉方向轻擦2次，叶片下方用手掌支撑，病毒浓度10μg/mL，接种后用流水冲洗。3d后记录病斑数，计算防效。
5、活体治疗作用：
选长势均匀一致的3–5叶期珊西烟，用毛笔全叶接种病毒，病毒浓度为10μg/mL，接种后用流水冲洗。叶面收干后，全株喷雾施药，每处理3次重复，并设1‰吐温80水溶液对照。3d后记录病斑数，计算防效。
6、活体钝化作用：
选长势均匀一致的3–5叶期珊西烟，将药剂与等体积的病毒汁液混合钝化30min后，摩擦接种，病毒浓度20μg/mL，接种后即用流水冲洗，重复3次，设1‰吐温80水溶液对照。3d后数病斑数，计算结果。
抑制率(％)＝[(对照枯斑数-处理枯斑数)/对照枯斑数]×100％
表1 Naamine及Naamidine类生物碱I-1～I-8的抗TMV活性测试结果：
从表1中可见Naamine及Naamidine类生物碱I-1～I-8表现出一定的抗TMV活性，I-1抗TMV活性较好，超过了病毒唑，具备极大的开发价值。
实施例3：抗菌活性测试，测定程序如下：
A.离体杀菌测试，菌体生长速率测定法(平皿法)：
将一定量药剂溶解在丙酮内，然后用含有200ug/mL乳化剂水溶液稀释至所需浓度，然后各吸取1mL药液注入培养皿内，再分别加入9mL培养基，摇匀后制成50ug/mL的含药平板，以添加1mL灭菌水的平板做空白对照。用直径4mm的打孔器沿菌丝外缘切取菌盘，移至含药平板上。每处理重复三次。将培养皿放在24±1℃恒温培养箱内培养。48小时后调查各处理菌盘扩展直径，求平均值，与空白对照比较计算相对抑菌率。
表2 Naamine及Naamidine类生物碱I-1～I-8的离体杀菌活性测试结果：
由表2中数据可以看出，Naamine及Naamidine类生物碱I-1～I-8表现出很好的抗植物病菌活性，化合物I-1对辣椒疫霉的抑制率达到70％以上，化合物I-2对小麦纹枯的抑制率达到了70％以上，而这两种病菌病危害极大，防治一直是个难题。
B.活体杀菌测试，植株喷雾法：
称量各化合物，定量DMSO(二甲基亚砜)溶解后加入1‰吐温80水溶液，配制成所需浓度待测液。
供试黄瓜、小麦幼苗培养于南开大学生测楼日光温室。黄瓜第一片真叶完全展开后，喷雾处理，喷液量1mL/处理，喷雾压力0.7kg/cm2，喷雾距离15cm。小麦一叶一心期处理，方法与黄瓜处理过程相同。
药剂处理后24h，黄瓜灰霉与黄瓜霜霉均采用喷雾接种5×105个/mL的孢子囊悬浮液于药剂处理后的黄瓜真叶叶背，至叶片呈水浸状止。暗环境保湿培养24h，后移至温室环境下正常培养。48h后调查结果。小麦苗则采用沉降接种法，接菌后7d调查结果。结果调查采用分级方法，以“100”级代表无病，即抑制率100％；“0”级代表最严重的发病程度，抑制率为0，记录。
表3 Naamine及Naamidine类生物碱I-1～I-8的活体杀菌活性测试结果：
从表3中数据可以看出，Naamine及Naamidine类生物碱I-1～I-8同样表现出不错的活体杀菌活性。
感谢国家自然科学基金(21402142)，天津市应用基础计划项目(15JCQNJC05600)和天津师范大学人才引进基金(5RL125)资助。
以上对本发明做了示例性的描述，应该说明的是，在不脱离本发明的核心的情况下，任何简单的变形、修改或者其他本领域技术人员能够不花费创造性劳动的等同替换均落入本发明的保护范围。
Claims (2)
1.一种Naamine及Naamidine类生物碱在治疗植物烟草花叶病毒中的应用，所述Naamine及Naamidine类生物碱为下述I-1～I-8结构式中的一种：
I-1结构式的处理计量为100～500μg/mL；
I-2～I-8结构式的处理计量为500μg/mL。
2.一种Naamine及Naamidine类生物碱在治疗植物病菌中的应用，所述Naamine及Naamidine类生物碱为下述I-1～I-8结构式中的一种：
所述植物病菌为黄瓜枯萎、花生褐斑 、苹果轮纹、小麦纹枯、玉米小斑、西瓜炭疽、水稻恶苗、番茄早疫、小麦赤霉、马铃薯晚疫、辣椒疫霉、油菜菌核、黄瓜灰霉和水稻纹枯。
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| WO2012041934A1 (en) * | 2010-09-28 | 2012-04-05 | Katholieke Universiteit Leuven | Polysubstituted 2-aminoimidazoles for controlling biofilms and process for their production |
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| WO2012041934A1 (en) * | 2010-09-28 | 2012-04-05 | Katholieke Universiteit Leuven | Polysubstituted 2-aminoimidazoles for controlling biofilms and process for their production |
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