CN109717198A - 一种a环修饰的新白叶藤碱衍生物在防治农业植物病害中的应用 - Google Patents
一种a环修饰的新白叶藤碱衍生物在防治农业植物病害中的应用 Download PDFInfo
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Abstract
本发明涉及天然药物化学领域和生物农药技术领域,公开了一种A环修饰的新白叶藤碱衍生物ZX‑1~ZX‑12任一化合物在制备防治或抗农业植物病害中的应用。生物活性测试发现,本发明所述化合物对油菜菌核病,立枯丝核菌,番茄灰霉病,小麦赤霉病,稻瘟病,西瓜蔓枯病6种植物病害表现出显著的抑制活性,且部分化合物对病菌的抑制活性优于嘧菌酯,可作为天然源生物碱杀菌剂的先导分子开发。由于本发明的化合物源于植物白叶藤(C.sanguinolenta)中的天然结构衍生物,具有无公害、安全高效的特点,具备天然源农药的优点能够开发为适用于为生产绿色、无污染农产品的植物源农药,属于新型生物源农药。
Description
技术领域
本发明属于天然药物化学领域和生物农药技术领域,公开了一种A环修饰的新白叶藤碱衍生物的新用途,具体涉及衍生物ZX-1~ZX-12在防治由油菜菌核病,立枯丝核菌,番茄灰霉病,小麦赤霉病,稻瘟病,西瓜蔓枯病引起的植物病害中的应用。
背景技术
目前,由真菌引起的植物病害主要以化学防治为主,虽然目前许多商品化杀菌剂防治效果较好,但由于这些化学农药的广泛使用,导致“3R”问题日趋严重,已引起了社会的极大关注。因此,研究与开发能有效控制有害生物的高效、低毒、低残留的新型农药,已成为目前农药创制的首要目标。植物源农药作为生物源农药的一部分,因公认其具有低毒、无残留、选择性高、易分解、不易产生抗药性等优点,而成为农药研究与开发的热点之一。因此,从植物资源中寻找和筛选潜在的杀菌次生代谢产物,并以其为先导结构进行结构优化设计正在成为新型杀菌剂创制的重要途径之一。植物真菌性病害一直是作物生产和产品储藏过程中的制约因素之一,对于产品的发育阶段、营养价值、有限保质期等问题方面都造成了严重损失。我国人口众多,粮食问题是我们亟待解决的重要问题之一。而我国的主要粮食作物小麦和水稻,小麦赤霉病病菌和稻瘟病病菌在这两种粮食作物中作为代表性真菌病害作为我们选择的对象。另外,我们还选择了4种重要性病害油菜菌核病病菌、立枯丝核菌病菌、番茄灰霉病病菌、西瓜蔓枯病病菌作为我们筛选的对象。
新白叶藤碱是源自非洲传统草药血红白叶藤(Cryptolepis sanguinolenta)中分离得到的天然生物碱之一,由于血红白叶藤在非洲被用来治疗黄疽、肝炎、胃肠疾病、阿米巴痢疾以及各种原因的发热,如疟疾、尿道与上呼吸道感染、风湿病和性病引起的发热,因而其次生代谢产物新白叶藤碱得以广泛关注,用于抗疟、抗菌、抗真菌、抗病毒和抗肿瘤等生物活性的先导化合物来研究与开发。课题组前期研究(中国发明专利,专利号:201810647499.3)发现新白叶藤碱B环修饰的衍生物对稻瘟病、油菜菌核和番茄灰霉表现出潜在的抑制作用,在该研究启发下,我们课题组继续对新白叶藤碱的杀菌构效关系进行了分析研究,发现保持B环不变,在A环进行为多样性结构优化合成,使其杀菌活性有了更为显著的提高,据此,本发明仍以新白叶藤碱为线索,重点进行A环修饰与优化合成,设计合成了一系列新分子,并发现目标化合物对油菜菌核病,立枯丝核菌,番茄灰霉病,小麦赤霉病,稻瘟病,西瓜蔓枯病具有优异的抑菌效果,可作为一种新型的广谱杀菌剂来开发。
发明内容
本发明目的是针对现有技术存在的缺陷,为农业生产提供一种A-环修饰的高活性新白叶藤碱衍生物的新用途,即新白叶藤碱衍生物作为生物农药在防治油菜菌核病、立枯丝核菌、番茄灰霉病、小麦赤霉病、稻瘟病、西瓜蔓枯病中的应用。
为实现上述目的,本发明提供了如下技术方法:一种抗油菜菌核病、立枯丝核菌、番茄灰霉病、小麦赤霉病、稻瘟病、西瓜蔓枯病的药物,其中含有治疗有效量的ZX-1~ZX-12中的任一化合物所示的新白叶藤碱衍生物。
本发明所述的一种A环修饰的新白叶藤碱衍生物ZX-1~ZX-12制备方法如图2所示。
本发明所述的新白叶藤碱衍生物合成方法见实施例,经多次硅胶柱层析等常规方法分离获得纯品,经质谱和核磁共振等波谱技术,确定了权利要求的喹啉类化合物ZX-1~ZX-12,其结构式如图1所示。经活性筛选结果表明,本发明所述的新白叶藤碱衍生物对油菜菌核病、立枯丝核菌、番茄灰霉病、小麦赤霉病、稻瘟病、西瓜蔓枯病表现出较强的抑制作用,可用于制备杀菌剂。
天然源生物碱具有高效、低毒、无污染、对人畜安全、作用方式独特、选择性高、对天敌和有益生物安全及害虫、病原菌不易产生抗药性等优点,符合人们对理想农药的要求。新白叶藤碱作为一类天然源生物碱属于生物农药,其本发明所述的优点在于:
1)杀菌活性高,可作为新的防治植物源病菌先导对其进行合理性开发。
2)本发明提供的化合物对油菜菌核病、立枯丝核菌、番茄灰霉病、小麦赤霉病、稻瘟病、西瓜蔓枯病具有优异的抑菌作用,为农业病菌防治提供了一种天然源杀菌活性物质。将其作为杀菌剂,其高效、低毒、安全等特点符合当前新农药创制的要求。
3)本发明化合物合成工艺简单、产品纯度高。
附图说明
图1新白叶藤碱衍生物
图2新白叶藤碱合成反应式
具体实施方式
为了更好地理解本发明,以下通过具体实施方式,对本发明的上述内容做进一步的详细说明。但不应将此理解为对本发明的限制。下列实施例中所述实验方法,如无特殊说明,均为常规方法。
实施例1:化合物ZX-1的合成
本发明所述化合物ZX-1的合成方法按如下反应式进行:
目标化合物ZX-1的合成:将邻甲氨基苯甲醛(0.5mmol)溶于适量乙醇中,随后加入吲哚(0.5mmol)和对甲苯磺酸(0.5mmol),加热回流24h。待冷却至室温后,用NaOH(1M)溶液调PH至碱性,随后用二氯甲烷萃取3次,收集有机相并用无水硫酸镁干燥,旋蒸除去二氯甲烷,柱层析(二氯甲烷/甲醇=50:1)纯化,得橙红色固体,即目标化合物ZX1(合成方法参见文献:ChemicalScience,2011,2,2178–2181)。
橙红色固体;产率:62%;m.p.105.32-106.54℃;1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.03(d,J=7.5Hz,1H),7.94(dd,J=8.0,1.5Hz,1H),7.75–7.64(m,2H),7.61(d,J=7.9Hz,1H),7.48(td,J=7.6,1.3Hz,1H),7.36(ddd,J=7.9,6.7,1.3Hz,1H),7.15(td,J=7.4,1.1Hz,1H),4.14(s,3H).13C NMR(101MHz,DMSO-d6)δ155.72,155.70,136.85,130.81,130.18,129.13,129.02,127.24,124.30,122.01,121.74,120.52,119.57,117.61,115.00,32.96.MS-ESI m/z:calcd for C16H12N2:232.10[M+H]+.
实施例2:化合物ZX-2的合成
合成方法与实施例1相同,仅以5-氟-2-(甲氨基)苯甲醛代替邻甲氨基苯甲醛。
橙红色固体;产率:70%;m.p.143.46-144.16℃;1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.10(d,J=7.6Hz,1H),7.97(ddd,J=12.6,9.2,3.8Hz,2H),7.71(td,J=8.8,3.0Hz,1H),7.58(d,J=7.9Hz,1H),7.50(t,J=7.6Hz,1H),7.18(t,J=7.4Hz,1H),4.28(s,3H).13C NMR(101MHz,DMSO-d6)δ156.04,155.68,133.82,129.61,128.51,128.27,123.89,121.99,121.28,119.72,119.20,118.95,117.63,117.42,114.44,33.45.MS-ESI m/z:calcd for C16H11FN2:250.09[M+H]+.
实施例3:化合物ZX-3的合成
合成方法与实施例1相同,仅以5-氯-2-(甲氨基)苯甲醛代替邻甲氨基苯甲醛。
红色固体;产率:50%;m.p.166.28-166.78℃;1H NMR(400MHz,DMSO-d6)δ8.83(d,J=5.5Hz,1H),8.18(t,J=3.5Hz,1H),8.10(d,J=7.5Hz,1H),7.96(d,J=9.0Hz,1H),7.81(dt,J=6.7,3.3Hz,1H),7.59(d,J=7.9Hz,1H),7.50(t,J=7.6Hz,1H),7.19(t,J=7.4Hz,1H),4.26(d,J=4.1Hz,3H).13C NMR(101MHz,DMSO-d6)δ155.93,155.62,135.66,130.57,129.66,128.80,128.45,128.06,126.21,124.09,122.00,121.71,119.94,117.78,117.41,33.37.MS-ESI m/z:calcd for C16H11ClN2:266.06[M+H]+.
实施例4:化合物ZX-4的合成
合成方法与实施例1相同,仅以5-甲基-2-(甲氨基)苯甲醛代替邻甲氨基苯甲醛。
红色固体;产率:51%;m.p.123.83-124.43℃;1HNMR(400MHz,DMSO-d6)δ8.81(s,1H),8.12(d,J=7.5Hz,1H),7.88–7.81(m,2H),7.63(dd,J=8.7,2.0Hz,1H),7.57(d,J=7.9Hz,1H),7.47(t,J=7.6Hz,1H),7.16(t,J=7.4Hz,1H),4.26(s,3H),2.47(s,3H).13CNMR(101MHz,DMSO-d6)δ155.77,155.72,135.27,132.49,131.36,129.59,129.08,129.01,127.31,124.30,121.79,120.65,119.42,117.51,115.19,33.12,20.78.MS-ESI m/z:calcdfor C17H14N2:246.12[M+H]+.
实施例5:化合物ZX-5的合成
合成方法与实施例1相同,仅以5-甲氧基-2-(甲氨基)苯甲醛代替邻甲氨基苯甲醛。
红色固体;产率:43%;m.p.131.52-134.62℃;1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.11(d,J=7.5Hz,1H),7.90(d,J=9.3Hz,1H),7.62(d,J=2.9Hz,1H),7.56(d,J=7.9Hz,1H),7.48(ddd,J=8.7,5.1,2.3Hz,2H),7.15(t,J=7.4Hz,1H),4.28(s,3H),3.90(s,3H).13C NMR(101MHz,DMSO-d6)δ155.96,155.48,154.45,131.96,129.18,128.67,127.70,124.02,121.78,121.46,120.70,119.23,117.43,116.71,110.82,56.03,33.28.MS-ESI m/z:calcd for C17H14N2O:262.11[M+H]+.
实施例6:化合物ZX-6的合成
合成方法与实施例1相同,仅以4-甲基-2-(甲氨基)苯甲醛代替邻甲氨基苯甲醛。
红色固体;产率:55%;m.p.172.19-174.69℃;1H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.11(d,J=7.6Hz,1H),8.01(d,J=8.1Hz,1H),7.77(s,1H),7.58(d,J=7.9Hz,1H),7.47(t,J=7.6Hz,1H),7.31(d,J=8.1Hz,1H),7.17(t,J=7.4Hz,1H),4.28(s,3H),2.59(s,3H).13C NMR(101MHz,DMSO-d6)δ155.88,155.48,141.66,137.24,130.17,129.33,128.84,126.33,124.44,123.87,121.61,119.51,118.66,117.54,115.11,33.11,22.43.MS-ESI m/z:calcd for C17H14N2:246.12[M+H]+.
实施例7:化合物ZX-7的合成
合成方法与实施例1相同,仅以4-氯-2-(甲氨基)苯甲醛代替邻甲氨基苯甲醛。
红色固体;产率:43%;m.p.181.13-183.33℃;1H NMR(400MHz,DMSO-d6)δ8.95(d,J=9.6Hz,1H),8.14(dd,J=10.2,7.9Hz,2H),8.05(d,J=1.9Hz,1H),7.60(d,J=8.0Hz,1H),7.55–7.46(m,2H),7.20(t,J=7.3Hz,1H),4.31(d,J=12.8Hz,3H).13C NMR(101MHz,DMSO-d6)δ155.69,155.65,137.82,135.71,131.94,129.45,128.84,127.69,124.29,122.52,121.94,120.06,119.44,117.82,115.14,33.41.MS-ESI m/z:calcd forC16H11ClN2:266.06[M+H]+.
实施例8:化合物ZX-8的合成
合成方法与实施例1相同,仅以4-氟-2-(甲氨基)苯甲醛代替邻甲氨基苯甲醛。
红色固体;产率:62%;m.p.91.14-94.24℃;1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.20(dd,J=8.8,6.4Hz,1H),8.12(d,J=7.6Hz,1H),7.83(dd,J=11.8,2.5Hz,1H),7.59(d,J=7.9Hz,1H),7.49(t,J=7.6Hz,1H),7.37(td,J=8.6,2.5Hz,1H),7.19(t,J=7.4Hz,1H),4.26(s,3H).13C NMR(101MHz,DMSO-d6)δ155.88,155.35,138.52,132.85,132.74,129.04,126.74,124.39,121.73,119.96,117.77,110.94,110.70,102.12,101.84,33.51.MS-ESI m/z:calcd for C16H11FN2:250.09[M+H]+.
实施例9:化合物ZX-9的合成
合成方法与实施例1相同,仅以3-甲基-2-(甲氨基)苯甲醛代替邻甲氨基苯甲醛。
暗红色固体;产率:27%;m.p.128.75-130.85℃;1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.09(d,J=7.5Hz,1H),7.93(dd,J=8.0,1.6Hz,1H),7.58(dd,J=7.8,5.4Hz,2H),7.47(t,J=7.7Hz,1H),7.35(t,J=7.5Hz,1H),7.17(t,J=7.4Hz,1H),4.50(s,3H),2.96(s,3H).13C NMR(101MHz,DMSO-d6)δ157.88,155.61,138.01,135.65,130.38,129.31,129.12,126.73,126.25,124.28,122.49,122.34,121.79,119.70,117.59,39.74,24.60.MS-ESI m/z:calcd for C17H14N2:246.12[M+H]+.
实施例10:化合物ZX-10的合成
合成方法与实施例1相同,仅以3-氟-2-(甲氨基)苯甲醛代替邻甲氨基苯甲醛。
红色固体;产率:57%;m.p.114.84-115.94℃;1H NMR(400MHz,DMSO-d6)δ8.92(d,J=1.9Hz,1H),8.12(d,J=7.5Hz,1H),7.93(d,J=7.9Hz,1H),7.65(ddd,J=15.4,8.0,1.5Hz,1H),7.59(d,J=7.9Hz,1H),7.55–7.47(m,1H),7.43(td,J=7.9,4.3Hz,1H),7.20(t,J=7.3Hz,1H),4.48(d,J=8.3Hz,3H).13C NMR(101MHz,DMSO-d6)δ156.40,155.63,129.66,129.10,128.06,126.79,126.34,124.13,123.58,122.54,122.07,120.11,117.95,117.79,117.73,37.29.MS-ESI m/z:calcd for C16H11FN2:250.09[M+H]+.
实施例11:化合物ZX-11的合成
合成方法与实施例1相同,仅以6-氯-2-(甲氨基)苯甲醛代替邻甲氨基苯甲醛。
红色固体;产率:21%;m.p.162.05-165.25℃;1H NMR(400MHz,DMSO-d6)δ9.08(d,J=10.2Hz,1H),8.25(p,J=7.9,6.9Hz,1H),7.92(t,J=9.5Hz,1H),7.76(t,J=8.4Hz,1H),7.66–7.44(m,3H),7.17(dt,J=14.2,7.4Hz,1H),4.28(m,3H).13C NMR(101MHz,DMSO-d6)δ155.96,138.18,132.87,130.98,129.81,128.50,124.31,122.80,122.53,120.05,117.96,117.74,114.99,40.20,39.78,33.74.MS-ESI m/z:calcd for C16H11ClN2:266.06[M+H]+.
实施例12:化合物ZX-12的合成
合成方法与实施例1相同,仅以6-甲基-2-(甲氨基)苯甲醛代替邻甲氨基苯甲醛。
红色固体;产率:34%;m.p.167.53-169.43℃;1HNMR(400MHz,DMSO-d6)δ9.05(s,1H),8.22(d,J=7.5Hz,1H),7.77(d,J=8.7Hz,1H),7.69(dd,J=8.7,7.1Hz,1H),7.59(d,J=7.9Hz,1H),7.51–7.45(m,1H),7.32(d,J=7.1Hz,1H),7.22–7.15(m,1H),4.27(s,3H),2.79(s,3H).13C NMR(101MHz,DMSO-d6)δ155.77,155.47,137.49,137.35,130.62,129.04,126.79,125.90,124.59,123.55,122.01,119.48,119.42,117.50,113.52,33.40,19.92.MS-ESI m/z:calcd for C17H14N2:246.12[M+H]+.
实施例13:新白叶藤碱衍生物对植物源病菌的抑菌活性测定及结果
1)供试药剂:新白叶藤碱衍生物ZX-1~ZX-12。
2)供试菌种:稻瘟病菌、油菜菌核病菌、立枯丝核菌、小麦赤霉病菌、西瓜蔓枯病菌和番茄灰霉病菌由甘肃省农业科学院提供。
3)生物测定方法:PDA培养基的配制方法:1.称重和熬煮按培养基配方逐一称取去皮土豆,土豆切成小块放入锅中,加水1000mL,在加热器上加热至沸腾,维持20-30min,用两层纱布趁热在量杯中过滤,弃掉滤渣,滤液用水稀释到1000mL。2.加热、溶解把滤液放入锅中,加葡萄糖20g,琼脂15g,然后放在电磁炉上小火加热,并用玻璃棒不断搅拌,以防治琼脂成团。待完全溶解后再补水至所需量。3.分装将配制好的培养基分装于100mL规格的锥形瓶中(固体培养基以不超过其溶剂的一半为宜)4.加棉塞培养基分装完毕后,在锥形瓶上封上封口膜,以阻止外界微生物进入培养基造成污染,并保证良好的通气性。5.灭菌将培养基置于压力蒸汽灭菌器上,以121℃灭菌3h,压力为0.15MPa。6.制备培养基(含药无菌操作台)将培养基以20mL量分装于培养皿中,静置,冷却,待其凝固。7.上样(接种)将无菌操作台进行灭菌操作,点燃酒精灯,采用插空法,通过点样针将所需菌种在酒精灯外焰接种于培养皿中,用胶带封口(打空器、点样针等仪器放入乙醇中灭菌)。8.培养将接种后的培养皿放入培养箱中进行培养。观察记录现象。计算抑菌率。分别测定新白叶藤碱系列化合物在25mg/L和50mg/L对6种菌的抑制活性,每个浓度做3个重复实验(结果见表-1)。
表1化合物ZX-1~ZX-12对6种植物病害的抑菌活性
由表1生测结果可知,本发明制备的新白叶藤碱衍生物ZX-1~ZX-12表现出优异的抑制活性,其中大部分化合物在50ppm下对6种病菌抑制活性达90%以上,甚至表现出更好的抑制活性。且本发明所述的新白叶藤碱衍生物结构简单,易于合成,其部分化合物的抑菌活性高于对照药嘧菌酯的抑菌活性,具有进一步研究的价值,有望开发成为新型的植物源农药,因而本发明所述的化合物可用于制备农药中的用途。
Claims (8)
1.本发明涉及一种A环修饰的新白叶藤碱衍生物在制备防治或抗农业病害的药物中的应用,是新白叶藤碱衍生物的新用途。
2.根据权利要求1所述的新白叶藤碱衍生物ZX-1~ZX-12具有如下的分子结构特征:。
3.根据权利要求1所述的新白叶藤碱衍生物ZX-1~ZX-12任一化合物在制备防治或抗油菜菌核病的药物中的应用。
4.根据权利要求1所述的新白叶藤碱衍生物ZX-1~ZX-12任一化合物在制备防治或抗立枯丝核菌引起的病害的药物中的应用。
5.根据权利要求1所述的新白叶藤碱衍生物ZX-1~ZX-12任一化合物在制备防治或抗番茄灰霉病的药物中的应用。
6.根据权利要求1所述的新白叶藤碱衍生物ZX-1~ZX-12任一化合物在制备防治或抗小麦赤霉病的药物中的应用。
7.根据权利要求1所述的新白叶藤碱衍生物ZX-1~ZX-12任一化合物在制备防治或抗稻瘟病的药物中的应用。
8.根据权利要求1所述的新白叶藤碱衍生物ZX-1~ZX-12任一化合物在制备防治或抗西瓜蔓枯病的药物中的应用。
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CN114304169A (zh) * | 2020-09-30 | 2022-04-12 | 兰州大学 | 一种含有白叶藤碱类似物和小分子酚类化合物的杀菌组合物及其在防治植物病害中的应用 |
CN114304169B (zh) * | 2020-09-30 | 2024-02-20 | 兰州大学 | 一种含有白叶藤碱类似物和小分子酚类化合物的杀菌组合物及其在防治植物病害中的应用 |
CN112889832A (zh) * | 2021-01-21 | 2021-06-04 | 兰州大学 | 一种含有白叶藤碱类似物和小分子萜烯类化合物的组合物在防治植物病害中的用途 |
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