CN113999231B - 骆驼宁碱a衍生物及其制备和在防治植物病毒病菌病中的应用 - Google Patents
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Abstract
本发明涉及骆驼宁碱A衍生物I‑1~I‑12及其制备方法和在防治植物病毒病菌病中的应用。本发明的色胺酮类衍生物I‑1~I‑12显示出抗植物病毒活性,能很好地抑制烟草花叶病毒,同时该类化合物也表现出广谱的抗植物病菌活性,且对苹果轮纹病菌的抑制活性突出。
Description
技术领域
本发明涉及骆驼宁碱A衍生物及其制备和在防治植物病毒病菌病中的应用,属于农业防护技术领域。
背景技术
2007年,美国奥尔巴尼分子研究公司Jason Herr(Bioorg.Med.Chem.2007,15,4237-4246.)等发现3-氟骆驼宁碱A对Topo I具有较强的抑制活性,与CPT的抑制活性相当,但与CPT的细胞毒性没有直接关系。3-N,N-二乙胺乙氧基和3-N,N-二甲基氨基乙氧基骆驼宁碱A对HCT-116肿瘤细胞(人结肠癌细胞系)毒性有改善作用。值得注意的是,2004年,米兰大学Dallavalle课题组(Bioorg.Med.Chem.Lett.2004,14,5757-5761.)发现2,3-二甲氧基骆驼宁碱A经topo-I介导的DNA***对H460(人非小肺癌细胞系)具有较强的细胞毒性,可能会对骆驼宁碱的结构改造提供新的思路。另一方面,2004年,印度有机化学国家重点实验室Chavan课题组(Tetrahedron Lett.2004,60,9931-9935.),发现14-乙基骆驼宁碱A与骆驼宁碱A相比,细胞毒性略有改善。此外,2010年俄罗斯内斯梅亚诺夫有机元素化合物研究所Golubev课题组(Russ.Chem.Bull.2010,59,209-218.)发现14-三氟甲基骆驼宁碱A引起体外培养的结肠腺癌细胞和白血病细胞凋亡,也显示出抑制Topo I的活性。
发明内容
针对现有技术不足,本发明提供骆驼宁碱A衍生物及其制备方法和在防治植物病毒病菌病中的应用。本专利的骆驼宁碱A衍生物具有很好的抗植物病毒和病菌活性。
本发明的骆驼宁碱A衍生物I为下述I-1~I-12所示的化合物(结构式一)。结构式I-1~I-12的合成方法如下:
骆驼宁碱A衍生物I-1~I-11的合成:按照方程式一所示的方法制备,首先以三氯甲烷做溶剂,三乙胺做碱,邻氨基苯甲酰胺(1)和邻硝基苯甲酰氯(2)室温生成中间体3,然后将中间体3溶在10%KOH水溶液∶乙醇=2∶1的溶液中,80℃加热回流生成中间体4,然后以乙醇为溶剂,在氯化亚锡二水合物(5)的作用下,90℃加热回流生成中间体6,最后在离子液体[BmIm]Br作用下,中间体6与相应的醛反应生成I-1~I-11。
结构式一
方程式一
骆驼宁碱A衍生物I-12的合成:按照方程式二所示的方法制备,以DMF做溶剂,在氧气作用下,化合物8在100℃加热条件下生成I-12。
方程式二
本发明的骆驼宁碱A衍生物I-1~I-12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,水稻稻瘟,辣椒疫霉,油菜菌核,黄瓜灰霉,水稻纹枯14种植物病菌。
具体实施方式
实施例1:骆驼宁碱A衍生物I-1~I-12的合成
第一步,中间体3的合成。将邻氨基苯甲酰胺(1)(5g,37mmol)溶在氯仿中,加入三乙胺(14mL),搅拌下缓慢加入邻硝基苯甲酰氯(2)(7mL,52mmol),室温反应四小时,TLC检测反应结束,减压抽滤得白色固体4.2g,收率80%,熔点195-197℃,1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),8.48(d,J=8.2Hz,1H),8.38(brs,1H),8.11(d,J=8.1Hz,1H),7.92-7.75(m,5H),7.59(t,J=7.7Hz,1H),7.23(t,J=7.6Hz,1H).
第二步,中间体4的合成。将中间体3(4g,14mmol)溶在10%的KOH水溶液(40mL)和无水乙醇(20mL)中,90℃加热回流,TLC检测反应结束,将大部分溶剂旋干,用乙酸乙酯萃取,无水硫酸钠干燥,抽滤,减压脱溶得浅棕色固体3.4g,收率92%,熔点178-180℃,1H NMR(400MHz,DMSO-d6)δ12.89(s,1H),8.33-8.19(m,2H),8.00-7.83(m,4H),7.71(d,J=8.2Hz,1H),7.64(t,J=7.5Hz,1H).13C NMR(100MHz,DMSO-d6)δ161.6,151.8,148.4,147.4,134.7,133.9,131.5,131.4,129.2,127.3,127.1,125.9,124.5,121.1.
第三步:中间体6的合成。将中间体4(1.2g,4.5mmol)和SnCl2·2H2O(5)(5.1g,22.5mmol)溶在乙醇中(20mL),90℃加热回流,TLC检测反应结束,将大部分溶剂旋干,用乙酸乙酯萃取,无水硫酸钠干燥,抽滤,减压脱溶得黄色固体1g,收率80%,熔点155-157℃,1HNMR(400MHz,DMSO-d6)δ12.18(brs,1H),8.19(d,J=7.9Hz,1H),7.88(t,J=7.6Hz,1H),7.84-7.73(m,2H),7.55(t,J=7.5Hz,1H),7.26(t,J=7.6Hz,1H),7.12(brs,1H),6.89(d,J=8.3Hz,1H),6.66(t,J=7.5Hz,1H).13C NMR(100MHz,DMSO-d6)δ162.6,154.1,149.9,148.5,135.0,132.3,129.3,127.4,126.7,126.2,120.9,117.1,115.5,112.8.
第四步,骆驼宁碱A衍生物I-1~I-11。将中间体6(500mg,2.11mmol),相应的醛(7)(63mg,2.11mmol),I2(27mg,0.11mmol)溶在[BmIm]Br(4mL),80℃加热TLC检测反应结束,加水淬灭,减压抽滤得I-1~I-11。
I-1:黄色固体330mg,收率63%,熔点178-180℃,1H NMR(400MHz,MeOD-d4)δ8.27-8.16(m,2H),7.81-7.76(m,1H),7.71(d,J=8.0Hz,1H),7.48-7.42(m,1H),7.40-7.34(m,1H),6.99-6.92(m,1H),6.88(d,J=8.1Hz,1H),5.31(s,2H).13C NMR(100MHz,DMSO-d6)δ159.8,148.6,148.4,148.2,135.1,133.7,127.7,127.5,126.8,126.4,120.8,119.5,116.6,116.1,52.9.HRMS(ESI)calcd for C15H12N3O[M+H]+250.0975,found 250.0974.
I-2:黄色固体,收率65%,熔点116-118℃,1H NMR(400MHz,MeOD-d4)δ8.27-8.16(m,2H),7.83-7.76(m,1H),7.72(d,J=8.1Hz,1H),7.46(t,J=7.5Hz,1H),7.40-7.33(m,1H),6.90(t,J=7.6Hz,1H),6.84(d,J=8.1Hz,1H),6.32(q,J=6.1Hz,1H),1.43(d,J=6.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ159.5,148.1,147.3,145.7,135.1,134.1,127.5,127.4,126.8,126.4,120.5,118.9,116.4,115.1,59.3,19.9.HRMS(ESI)calcd forC16H14N3O[M+H]+264.1131,found 264.1131.
I-3:黄色固体,收率83%,熔点235-237℃,1H NMR(400MHz,DMSO-d6)δ8.17(d,J=7.6Hz,2H),7.83(t,J=7.6Hz,1H),7.70(d,J=8.2Hz,1H),7.57-7.44(m,2H),7.37(t,J=7.6Hz,1H),6.92(d,J=8.1Hz,1H),6.84(t,J=7.5Hz,1H),5.96-5.86(m,1H),1.78(d,J=10.0Hz,2H),1.69-1.44(m,3H),1.22-1.11(m,1H),1.11-0.88(m,5H).13C NMR(100MHz,DMSO-d6)δ160.2,148.0,147.6,145.6,135.2,134.1,127.5,127.2,126.3,120.5,118.6,115.9,115.8,65.9,28.7,28.7,26.0,25.5,25.5.HRMS(ESI)calcd for C21H22N3O[M+H]+332.1757,found 332.1757.
I-4:棕色固体,收率67%,熔点98-100℃,1H NMR(400MHz,CDCl3)δ8.32-8.26(m,1H),8.19(d,J=8.2Hz,1H),7.74-7.64(m,2H),7.42-7.31(m,2H),6.88(t,J=7.6Hz,1H),6.64(d,J=8.2Hz,1H),5.45-5.38(m,1H),3.60-3.50(m,1H),3.38-3.29(m,1H),3.28-3.18(m,1H),2.22-1.93(m,3H).13C NMR(100MHz,CDCl3)δ160.9,146.9,146.9,144.5,133.3,132.5,127.1,126.1,125.4,125.0,120.0,118.0,115.5,111.8,71.0,44.6,31.5,19.8.HRMS(ESI)calcd for C18H16N3O[M+H]+290.1288,found 290.1287.
I-5:绿色固体,收率65%,熔点193-195℃,1H NMR(400MHz,DMSO-d6)δ8.20(d,J=7.7Hz,1H),8.10(d,J=7.7Hz,1H),7.86(t,J=7.1Hz,1H),7.77(d,J=8.1Hz,1H),7.48(t,J=7.4Hz,1H),7.33(d,J=2.6Hz,1H),7.31-7.24(m,2H),6.89-6.78(m,2H),6.61(d,J=1.9Hz,1H),6.47(d,J=8.5Hz,1H),6.29-6.22(m,1H),3.90(s,3H),3.65(s,3H).13C NMR(100MHz,DMSO-d6)δ160.6,159.1,157.4,148.0,147.7,145.0,134.9,133.4,127.2,126.7,126.5,126.1,125.8,119.9,119.5,118.4,115.8,115.0,104.0,98.9,59.2,55.8,55.1.HRMS(ESI)calcd for C23H20N3O3[M+H]+386.1499,found 386.1500.
I-6:黄色固体,收率85%,熔点183-185℃,1H NMR(400MHz,CDCl3)δ8.11(t,J=6.9Hz,2H),7.81(d,J=8.6Hz,2H),7.58(s,2H),7.33-7.18(m,4H),7.16(t,J=7.5Hz,1H),6.80(t,J=7.6Hz,1H),6.67(d,J=8.0Hz,1H),5.13(s,1H).13C NMR(100MHz,CDCl3)δ160.8,148.2,147.9,146.5,146.2,142.7,135.0,133.8,127.9,127.8,127.3,127.1,126.6,123.9,121.6,120.4,118.2,117.1,62.8.HRMS(ESI)calcd for C21H15N4O3[M+H]+371.1139,found 371.1140.
I-7:黄色固体,收率84%,熔点114-116℃,1H NMR(400MHz,DMSO-d6)δ8.54-8.43(m,2H),8.23(d,J=7.2Hz,1H),8.15-8.07(m,2H),7.89(t,J=7.7Hz,1H),7.77(d,J=8.1Hz,1H),7.55(t,J=7.5Hz,1H),7.36(t,J=7.1Hz,1H),7.29(d,J=3.6Hz,1H),7.17(d,J=5.3Hz,2H),6.98(d,J=8.1Hz,1H),6.92-6.81(m,1H).13C NMR(100MHz,DMSO-d6)δ160.2,150.5,148.6,148.2,147.4,145.3,135.6,134.3,127.8,127.4,127.2,126.9,121.4,120.3,119.7,116.6,116.2,62.2.HRMS(ESI)calcd for C20H15N4O[M+H]+327.1240,found 327.1239.
I-8:黄色固体,收率72%,熔点211-213℃,1H NMR(400MHz,DMSO-d6)δ8.20(d,J=7.8Hz,2H),7.88(t,J=7.1Hz,1H),7.77(d,J=8.0Hz,1H),7.59(d,J=3.6Hz,1H),7.53(t,J=7.5Hz,1H),7.37(t,J=7.6Hz,1H),7.26(d,J=3.7Hz,1H),6.98-6.83(m,4H).13C NMR(100 MHz,DMSO-d6)δ159.6,147.8,147.5,144.9,144.4,134.8,133.2,127.2,126.8,126.5,126.0,120.3,119.3,116.4,116.3,58.4.HRMS(ESI)calcd for C18H14N5O3[M+H]+316.1193,found 316.1192.
I-9:棕色固体,收率88%,熔点153-155℃,1H NMR(400MHz,DMSO-d6)δ8.23-8.14(m,2H),7.93(d,J=3.0Hz,1H),7.88-7.82(m,1H),7.73(d,J=8.1Hz,1H),7.54-7.48(m,1H),7.45-7.34(m,2H),6.98(d,J=8.0Hz,1H),6.93-6.85(m,1H),6.74(d,J=3.4Hz,1H),6.57-6.53(m,1H),2.25(s,3H).13C NMR(100MHz,DMSO-d6)δ159.1,147.6,146.6,145.0,140.2,139.3,135.0,133.8,127.2,126.9,126.6,126.2,126.0124.6,119.9,119.1,116.1,115.3,59.9,14.7.HRMS(ESI)calcd for C20H16N3OS[M+H]+346.1009,found 346.1009.
I-10:棕色固体,收率78%,熔点168-170℃,1H NMR(400MHz,MeOD-d4)δ8.24(d,J=8.0Hz,2H),7.86-7.80(m,1H),7.76(d,J=8.1Hz,1H),7.50(t,J=7.5Hz,1H),7.38(t,J=7.1Hz,1H),7.26(s,1H),6.96-6.87(m,2H),6.21(d,J=3.4Hz,1H),6.05(d,J=3.3Hz,1H).13C NMR(100MHz,DMSO-d6)δ159.6,154.1,148.1,147.2,145.2,135.5,134.1,127.8,127.4,127.1,126.8,121.9,120.4,119.8,116.4,116.0,113.0,111.5,58.2.HRMS(ESI)calcd for C19H13BrN3O2[M+H]+394.0186,found 394.0185.
I-11:黄绿色固体,收率80%,熔点115-117℃,1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.26(d,J=7.0Hz,1H),8.13(dd,J=8.0,1.1Hz,1H),7.88-7.82(m,1H),7.78(d,J=3.0Hz,1H),7.73(d,J=7.9Hz,1H),7.54-7.45(m,2H),7.45-7.39(m,1H),6.97(dd,J=11.2,4.0Hz,1H),6.88(d,J=7.9Hz,1H),2.63(s,3H).13C NMR(100MHz,DMSO-d6)δ159.0,151.1,150.5,147.4,144.2,135.1,134.0,129.2,127.2,127.0,126.5,119.8,119.5,116.3,115.2,58.2,15.3.HRMS(ESI)calcd for C19H15N4OS[M+H]+347.0961,found347.0959.
实施例2:骆驼宁碱A衍生物I-12的合成
将化合物8(600mg,2mmol)溶在THF中,氧气保护,100℃加热TLC检测反应结束,用水稀释,甲基叔丁基醚萃取,无水硫酸钠干燥,抽滤,减压脱溶,柱层析(V(石油醚)∶V(乙酸乙酯)=10∶1)得浅黄色固体480mg,收率61%,熔点131-133℃,1H NMR(400MHz,CDCl3)δ8.82(d,J=7.9Hz,1H),8.23(d,J=8.0Hz,1H),7.87-7.76(m,4H),7.65(t,J=6.8Hz,1H),7.59(d,J=7.9Hz,1H),7.50-7.38(m,3H).13C NMR(100MHz,CDCl3)δ159.8,146.9,146.6,145.3,142.0,136.1,135.7,135.4,133.7,131.9,129.8,129.3,129.0,128.1,127.6,127.5,127.3,126.7,126.2,121.7,119.8.HRMS(ESI)calcd for C21H12Cl2N3O[M+H]+392.0352,found 392.0353.
实施例3: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,原药加入DMF溶解,制得1×105μg/mL母液,后用含1‰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、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1‰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。
4、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。
5、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%
首先在处理剂量500μg/mL条件下所有化合物的抗烟草花叶病毒活体钝化活性测试,将相对抑制率大于40%的化合物再进行处理剂量500μg/mL条件下的活体治疗和活性保护活性测试以及处理剂量100μg/mL条件下的抗烟草花叶病毒活体钝化、活体治疗、活体保护活性测试。阳性对照为商品化抗植物病毒药剂病毒唑和宁南霉素。
表1骆驼宁碱A衍生物I-1~I-12的抗烟草花叶病毒(TMV)活性测试结果:
从表中数据得出,骆驼宁碱A衍生物I-1~I-12在处理剂量为500μg/mL的浓度下都表现出不错的抗TMV活性,其中衍生物I-9、I-9、I-10都表现出与宁南霉素相当的抗TMV活性。
实施例4:抗菌活性测试,测定程序如下:
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适量丙酮内,然后用含有200μg/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50μg/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骆驼宁碱A衍生物I-1~I-12的抗植物病菌活性测试结果:
骆驼宁碱A衍生物在测试浓度为50μg/mL的条件下对14种被测试菌都表现出广谱的抑制活性。其中对苹果轮纹的抑菌活性较好,化合物I-6、I-11对苹果轮枯的抑制率均到达81%、I-3、I-6对小麦纹枯的抑制率分别为87%、81%,化合物I-9对辣椒疫霉的抑制率达89%,I-9、I-11对油菜菌核的抑制率均为85%。
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值,这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说,各个范围的端点值之间、各个范围的端点值和单独的点值之间,以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围,这些数值范围应被视为在本文中具体公开。
上述实施例中所涉及的原料和试剂均由商购或参考文献方法制备获得,化学反应工艺是本技术领域的技术人员所能掌握的。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于此。在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,包括各个技术特征以任何其它的合适方式进行组合,这些简单变型和组合同样应当视为本发明所公开的内容,均属于本发明的保护范围。
Claims (4)
1.一种色胺酮衍生物,其特征在于所述色胺酮衍生物为下述I-3~I-11结构中的一种:
2.权利要求1中I-3~I-11的制备方法:
骆驼宁碱A衍生物I-3~I-11的合成:按照方程式一所示的方法制备,首先以三氯甲烷做溶剂,三乙胺做碱,邻氨基苯甲酰胺(1)和邻硝基苯甲酰氯(2)室温反应4小时生成中间体3,然后将中间体3溶在10%KOH水溶液∶乙醇=2∶1的溶液中,80℃加热回流生成中间体4,然后以乙醇为溶剂,在氯化亚锡二水合物(5)的作用下,90℃加热回流生成中间体6,最后在离子液体[BmIm]Br作用下,中间体6与相应的醛在90℃ I2催化下发生缩合反应生成I-3~I-11,
方程式一。
3.权利要求1所述的色胺酮衍生物I-3~I-11在防治烟草花叶病毒病中的应用。
4.权利要求1所述的色胺酮衍生物I-3~I-11在防治植物病菌病中的应用,其特征在于它作为抗植物病菌剂,能抑制黄瓜枯萎,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,水稻稻瘟,辣椒疫霉,油菜菌核,黄瓜灰霉,水稻纹枯14种植物病菌。
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