CN115028635B - 一种骨架跃迁型小檗碱类似物及其在防治农业病害中的应用 - Google Patents
一种骨架跃迁型小檗碱类似物及其在防治农业病害中的应用 Download PDFInfo
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Abstract
本发明公开了一种骨架跃迁型小檗碱类似物,属于药物化学技术领域。本发明通过生物电子等排和骨架跃迁策略对小檗碱四环结构母核进行结构改造(反应化学式如下),最终制备如本申请所述的骨架跃迁小檗碱类似物,并进一步评价了其对立枯丝核菌、油菜菌核病菌、番茄灰霉病菌、小麦赤霉病菌、稻瘟病菌和辣椒疫霉病菌等植物病原真菌,以及水稻白叶枯ACCC 11602,柑橘溃疡病菌和马铃薯黑胫菌ACCC 19901等植物病原细菌的抗菌活性。测试结果表明,所合成的小檗碱类似物对病原细菌和真菌具有一定的抑制作用,特别是部分化合物对立枯丝核菌表现出高选择性的强效抗菌活性,有望进一步开发成为一种新型杀菌剂。
Description
技术领域
本发明属于药物化学领域,公开了一种骨架跃迁小檗碱类似物在抗菌方面的用途,具体涉及化合物E1~E29在防治由立枯丝核菌、油菜菌核病菌、番茄灰霉病菌、小麦赤霉病菌、稻瘟病菌和辣椒疫霉病菌等植物病原真菌,以及水稻白叶枯ACCC 11602,柑橘溃疡病菌和马铃薯黑胫菌ACCC 19901等植物病原细菌引起的病害中的用途。
背景技术
植物病原真菌和细菌不仅能侵染植物,引起作物大规模减产,给人类带来重大的经济损失,还会威胁环境和人类健康。因此,抗菌药物的研发是人们不可忽视的重点工作。然而,随着现有抗菌药物的大量滥用,越来越多的植物病原真菌和细菌对现有药物产生了严重的耐药性,使得病原真菌和细菌引起的病害变得更加难以控制。
小檗碱是一种从传统中药黄莲中分离得到的异喹啉类生物碱,具有广泛的生物活性,如抗炎、抗微生物、抗帕金森病、抗肿瘤、抗病毒等。研究表明,小檗碱对白色念珠菌,克鲁斯氏念珠菌,光滑念珠菌等病原真菌均有一定的抗真菌活性,其MIC值在10~160μg/mL之间。此外,以小檗碱为活性先导,通过在其不同结构位点进行取代修饰还能进一步提高其抗菌活性。因此,以天然产物小檗碱为先导结构寻找高效的抗菌化合物具有很大的开发潜力。
发明内容
本发明提供了一类针对立枯丝核菌、油菜菌核病菌、番茄灰霉病菌、小麦赤霉病菌、稻瘟病菌和辣椒疫霉病菌等植物病原真菌,水稻白叶枯ACCC 11602,柑橘溃疡病菌和马铃薯黑胫菌ACCC 19901等植物病原细菌的骨架跃迁型小檗碱类似物。本发明中的骨架跃迁型小檗碱类似物E1~E29化合物结构如化学式1所示,化学式1中的R1可为氢、氟、氯、溴、硝基、三氟甲基;R2可为氢、氟、氯、甲基、甲氧基;R3可为氢、三氟甲基;R4可为氢、溴、甲氧基;R5可为氢、氟、氯、溴、甲氧基。
本发明所述的小檗碱类似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小檗碱类似物E1~E29的结构。
具体地,所述小檗碱类似物的化学结构式为:
此外,本发明还请求保护上述骨架跃迁型小檗碱类似物在制备防治或抗立枯丝核菌的药物中的应用。
或,所述骨架跃迁型小檗碱类似物在制备防治或抗油菜菌核病菌的药物中的应用。
或,所述骨架跃迁型小檗碱类似物在制备防治或抗番茄灰霉病菌的药物中的应用。
所述骨架跃迁型小檗碱类似物在制备防治或抗小麦赤霉病菌的药物中的应用。
或,所述骨架跃迁型小檗碱类似物在制备防治或抗稻瘟病菌的药物中的应用。
或,所述骨架跃迁型小檗碱类似物在制备防治或抗辣椒疫霉病的药物中的应用。
或,所述骨架跃迁型小檗碱类似物在制备防治或抗水稻白叶枯ACCC 11602、柑橘溃疡病菌和马铃薯黑胫菌ACCC 19901等植物病原细菌的药物中的应用。
本发明所述的小檗碱类似物对立枯丝核菌、油菜菌核病菌、番茄灰霉病菌、小麦赤霉病菌、稻瘟病菌和辣椒疫霉病菌等植物病原真菌,水稻白叶枯ACCC 11602,柑橘溃疡病菌和马铃薯黑胫菌ACCC 19901等植物病原细菌表现出一定程度的抑制作用。
具体实施方式
下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。
实施例1:
化合物E1的合成
本发明所述化合物E1的合成方法按如下反应式进行:
目标化合物E1的合成:向干燥的DMF溶液(15mL)中加入吲哚-2-甲醛(1.0mmol)、2-氟苯胺(1.0mmol)和碳酸铯(3.0mmol),然后在120℃下搅拌9小时。反应完成后,将反应混合物倒入冰水中并用二氯甲烷萃取三次。合并有机相,旋干,所得粗产物在硅胶上通过柱色谱纯化,最终得到化合物E1。
黄色固体,产率:55%;1H NMR(500MHz,DMSO-d6)δ:9.11(s,1H),8.70(dd,J=8.4,2.2Hz,2H),8.05(d,J=7.9Hz,1H),7.96(m,1H),7.72(td,J=8.5,7.9,1.7Hz,1H),7.61-7.58(m,1H),7.55-7.46(m,2H),7.38(s,1H).13C NMR(125MHz,DMSO-d6)δ:148.64,135.87,132.39,130.55,130.41,129.80,129.71,129.11,127.89,125.06,124.83,123.24,115.77,115.41,101.62.MS-ESI m/z:calcd for C15H10N2[M+H]+:219.0844;found:219.0866.
实施例2:化合物E2的合成
合成方法与实施例1相同,仅以2,4-二氟苯胺代替2-氟苯胺。
黄色固体,产率:58%;1H NMR(500MHz,DMSO-d6)δ:9.05(s,1H),8.66(d,J=8.5Hz,1H),8.39(dd,J=10.5,2.7Hz,1H),8.03(d,J=7.9Hz,1H),7.97(dd,J=8.8,6.3Hz,1H),7.64-7.55(m,1H),7.51(d,J=7.6Hz,1H),7.43-7.29(m,2H).13C NMR(125MHz,DMSO-d6)δ:161.99(d,J=245.6Hz),147.84,132.66(d,J=2.5Hz),132.29,132.14(d,J=10.1Hz),131.18(d,J=11.9Hz),129.34,129.18,125.20,123.54,123.17,115.36,111.98(d,J=23.0Hz),102.84(d,J=28.1Hz),101.98.MS-ESI m/z:calcd for C15H9FN2[M+H]+:237.0750;found:237.0858.
实施例3:化合物E3的合成
合成方法与实施例1相同,仅以2,5-二氟苯胺代替2-氟苯胺。
黄色固体,产率:54%;1H NMR(500MHz,DMSO-d6)δ:9.13(s,1H),8.68(dd,J=9.2,5.0Hz,1H),8.63(d,J=8.7Hz,1H),8.04(d,J=8.0Hz,1H),7.74(dd,J=9.3,3.1Hz,1H),7.65-7.59(m,1H),7.53(td,J=8.6,3.1Hz,1H),7.49(t,J=7.5Hz,1H),7.39(s,1H).13CNMR(125MHz,DMSO-d6)δ:158.59(d,J=241.7Hz),149.95,137.20(d,J=11.1Hz),132.27,129.49,128.91,127.30(d,J=2.4Hz),125.33,123.33(d,J=12.1Hz),117.24(d,J=9.1Hz),116.52,116.33,115.80(d,J=22.2Hz),115.10,102.09.MS-ESI m/z:calcd forC15H9FN2[M+H]+:237.0750;found:237.0778.
实施例4:化合物E4的合成
合成方法与实施例1相同,仅以2-氟-5-氯苯胺代替2-氟苯胺。
黄色固体,产率:45%;1H NMR(500MHz,DMSO-d6)δ:9.10(s,1H),8.63(d,J=8.9Hz,1H),8.59(d,J=8.7Hz,1H),8.03(d,J=8.0Hz,1H),7.92(d,J=2.5Hz,1H),7.66(dd,J=8.9,2.5Hz,1H),7.63-7.56(m,1H),7.49(t,J=7.5Hz,1H),7.38(s,1H).13C NMR(125MHz,DMSO-d6)δ:149.97,136.98,132.34,129.50,129.34,129.22,129.06,128.98,128.29,125.40,123.43,123.40,117.35,115.23,102.46.MS-ESI m/z:calcd for C15H9ClN2[M+H]+:253.0454;found:253.0473.
实施例5:化合物E5的合成
合成方法与实施例1相同,仅以2-氟-4-氯苯胺代替2-氟苯胺。
黄色固体,产率:51%;1H NMR(500MHz,DMSO-d6)δ:9.10(d,J=1.1Hz,1H),8.63(d,J=8.5Hz,1H),8.56(t,J=2.1Hz,1H),8.05(d,J=8.1Hz,1H),7.94(dd,J=8.5,1.2Hz,1H),7.69-7.57(m,1H),7.55-7.46(m,2H),7.41(s,1H).13C NMR(125MHz,DMSO-d6)δ:148.98,134.68,133.58,132.34,131.72,131.25,129.50,129.15,125.49,124.85,123.58,123.30,115.37,115.12,102.40.MS-ESI m/z:calcd for C15H9ClN2[M+H]+:253.0454;found:253.0484.
实施例6:化合物E6的合成
合成方法与实施例1相同,仅以2-氟-5-溴苯胺代替2-氟苯胺。
黄色固体,产率:51%;1H NMR(500MHz,DMSO-d6)δ:9.11(d,J=1.6Hz,1H),8.70-8.56(m,2H),8.12-8.00(m,2H),7.80(d,J=8.9Hz,1H),7.65-7.57(m,1H),7.50(t,J=7.8Hz,1H),7.40(s,1H).13C NMR(125MHz,DMSO-d6)δ:149.97,137.27,132.39,132.18,131.83,129.76,129.52,129.12,125.46,123.49,123.46,117.70,116.15,115.31,102.55.MS-ESI m/z:calcd for C15H9BrN2[M+H]+:295.9949;found:296.9981.
实施例7:化合物E7的合成
合成方法与实施例1相同,仅以2,4,5-三氟苯胺代替2-氟苯胺。
黄色固体,产率:56%;1H NMR(500MHz,DMSO-d6)δ:9.09(s,1H),8.63(m,2H),8.03(d,J=8.1Hz,1H),7.97(t,J=9.7Hz,1H),7.59(t,J=7.9Hz,1H),7.50(t,J=7.6Hz,1H),7.39(s,1H).13C NMR(125MHz,DMSO-d6)δ:149.24,132.94-132.65(m),132.12,129.13,128.97,127.31-126.96(m),125.41,123.60,123.29,117.98(d,J=18.5Hz),115.16,108.17,104.96,104.77,102.38.MS-ESI m/z:calcd for C15H8F2N2[M+H]+:255.0656;found:255.0738.
实施例8:化合物E8的合成
合成方法与实施例1相同,仅以2-氟-5-三氟甲基苯胺代替2-氟苯胺。
黄色固体,产率:58%;1H NMR(500MHz,DMSO-d6)δ:9.14(s,1H),8.78(d,J=8.7Hz,1H),8.64(d,J=8.7Hz,1H),8.16(d,J=2.2Hz,1H),8.05(d,J=7.9Hz,1H),7.93(dd,J=8.7,2.3Hz,1H),7.63(m,1H),7.52(t,J=7.5Hz,1H),7.43(s,1H).13C NMR(125MHz,DMSO-d6)δ:150.34,135.68,133.13,132.56,129.63,129.30,126.88(d,J=3.9Hz),126.83,125.73,123.80,123.51,120.95,116.77,115.35,113.33,103.21.MS-ESI m/z:calcd forC16H9F3N2[M+H]+:287.0718;found:287.0791.
实施例9:化合物E9的合成
合成方法与实施例1相同,仅以2-氟-3-三氟甲基苯胺代替2-氟苯胺。
黄色固体,产率:62%;1H NMR(500MHz,DMSO-d6)δ:9.14(s,1H),8.14(d,J=7.8Hz,1H),8.02(m,3H),7.70(t,J=7.9Hz,1H),7.47(m,3H).13C NMR(125MHz,DMSO-d6)δ:149.59,138.31,137.44,133.21,132.23,129.05(d,J=4.6Hz),128.76,126.20,125.75,125.51,124.19,123.76,123.32,118.04(d,J=32.1Hz),113.54(d,J=5.7Hz),103.32.MS-ESI m/z:calcd for C16H9F3N2[M+H]+:287.0718;found:287.0803.
实施例10:化合物E10的合成
合成方法与实施例1相同,仅以2-氟-5-硝基苯胺代替2-氟苯胺。
黄色固体,产率:53%;1H NMR(500MHz,DMSO-d6)δ:9.16(s,1H),8.77(d,J=9.2Hz,1H),8.64(d,J=8.7Hz,1H),8.55(s,1H),8.40(d,J=9.2Hz,1H),8.05(d,J=8.0Hz,1H),7.64(t,J=7.8Hz,1H),7.52(t,J=7.5Hz,1H),7.47(s,1H).13C NMR(125MHz,DMSO-d6)δ:150.99,143.19,135.64,135.22,132.75,129.58,129.56,126.14,124.83,124.28,124.19,123.70,116.59,115.45,104.30.MS-ESI m/z:calcd for C15H9N3O2[M+H]+:264.0695;found:264.0793.
实施例11:化合物E11的合成
合成方法与实施例1相同,仅以2-氟-4-甲基苯胺代替2-氟苯胺。
黄色固体,产率:43%;1H NMR(500MHz,DMSO-d6)δ:9.02(s,1H),8.72(d,J=8.7Hz,1H),8.43(s,1H),8.02(d,J=8.1Hz,1H),7.82(d,J=8.1Hz,1H),7.64-7.55(m,1H),7.49(t,J=7.5Hz,1H),7.33(s,1H),7.30(dd,J=8.0,1.6Hz,1H),2.61(s,3H).13C NMR(125MHz,DMSO-d6)δ:147.48,139.97,133.86,132.32,130.40,130.13,129.90,129.13,125.76,124.79,123.16,123.06,115.63,115.58,101.18,21.91.MS-ESI m/z:calcd for C16H12N2[M+H]+:233.1000;found:233.1128.
实施例12:化合物E12的合成
合成方法与实施例1相同,仅以2-氟-4-甲氧基苯胺代替2-氟苯胺。
黄色固体,产率:48%;1H NMR(500MHz,DMSO-d6)δ:8.94(d,J=2.0Hz,1H),8.57(dd,J=8.7,2.4Hz,1H),8.02(d,J=8.1Hz,1H),7.96(t,J=2.6Hz,1H),7.87(dd,J=8.8,2.0Hz,1H),7.66-7.53(m,1H),7.48(t,J=7.6Hz,1H),7.30(d,J=2.0Hz,1H),7.10(dt,J=8.8,2.3Hz,1H),4.02(d,J=1.8Hz,3H).13C NMR(126MHz,DMSO-d6)δ:160.14,145.63,132.17,131.58,131.42,130.20,129.81,129.30,124.75,123.26,123.00,115.34,111.25,100.94,100.24,56.32.MS-ESI m/z:calcd for C16H12N2O[M+H]+:249.0950;found:249.1080.
实施例13:化合物E13的合成
本发明所述化合物E13的合成方法按如下反应式进行:
中间体b1的合成:先将5-氯吲哚-2-羧酸(5.0mmol)溶于干燥的THF溶液(80mL)中,然后在室温下少量多次的缓慢加入LiAlH4(10.0mmol)。室温搅拌6小时后,再次加入少量LiAlH4促使反应完全,直到通过TLC检测到原料全部消失。接着用80%的甲醇水溶液(4.0mL)使反应停止,所得悬浮液在真空中浓缩以除去反应液中的THF。所得浓缩物通过柱层析纯化后得到中间体b1。
中间体c1的合成:将上一步得到的中间体b1(3.0mmol)和活化的MnO2(30.0mmol)在室温下加入到二氯甲烷溶液(30ml)中。该反应液在室温下搅拌24小时后,过滤,所得滤液在真空中浓缩。浓缩后的粗品经柱层析纯化,最终得到中间体c1。
目标化合物E13的合成:将上一步合成得到的中间体c1、与各种2-氟苯胺(1.0mmol)和碳酸铯(3.0mmol)共同加入到干燥的DMF(15mL)中,然后在120℃下搅拌12小时。反应完成后,旋干DMF溶剂,再向反应混合物中倒入冰水,并用二氯甲烷萃取三次。合并的有机层,减压浓缩。所得粗产物经柱色谱纯化后,最终得到化合物E13。
黄色固体,产率:58%;1H NMR(500MHz,DMSO-d6)δ:9.22-8.94(m,1H),8.69(d,J=35.7Hz,2H),8.12(s,1H),7.98(s,1H),7.73(s,1H),7.55(s,2H),7.42-7.31(m,1H).13C NMR(126MHz,DMSO-d6)δ:148.48,135.84,130.82,130.75,130.59,130.31,130.10,129.96,127.78,125.24,124.77,122.12,117.11,115.80,101.09.MS-ESIm/z:calcd for C15H9ClN2[M+H]+:253.0454;found:253.0593.
实施例14:化合物E14的合成
合成方法与实施例13相同,仅以2-氟-5-氯苯胺代替2-氟苯胺。
黄色固体,产率:54%;1H NMR(500MHz,DMSO-d6)δ:9.18(s,1H),8.68(dd,J=9.1,5.6Hz,2H),8.15(d,J=2.2Hz,1H),8.00(d,J=2.6Hz,1H),7.72(dd,J=8.8,2.7Hz,1H),7.58(dd,J=9.0,2.3Hz,1H),7.41(s,1H).13C NMR(125MHz,DMSO-d6)δ:149.84,136.99,130.75,130.56,130.27,129.42,129.23,128.96,128.74,128.00,125.11,122.27,117.41,116.90,101.89.MS-ESI m/z:calcd for C15H8Cl2N2[M+H]+:287.0065;found:287.0188.
实施例15:化合物E15的合成
合成方法与实施例13相同,仅以2-氟-5-三氟甲基苯胺代替2-氟苯胺。
黄色固体,产率:62%;1H NMR(500MHz,DMSO-d6)δ:9.09(s,1H),8.62(d,J=8.7Hz,1H),8.53(d,J=9.1Hz,1H),8.11(d,J=2.1Hz,1H),8.00(d,J=2.1Hz,1H),7.88(dd,J=8.8,2.2Hz,1H),7.50(dd,J=9.1,2.2Hz,1H),7.30(s,1H).13CNMR(125MHz,DMSO-d6)δ:150.05,135.55,132.52,130.75,130.51,130.36,128.26,127.00(d,J=3.8Hz),125.82(d,J=3.8Hz),125.42,125.31,125.24,124.98,123.26,122.26,116.75(d,J=16.6Hz),102.49.MS-ESI m/z:calcd for C16H8ClF3N2[M+H]+:321.0328;found:321.0475.
实施例16:化合物E16的合成
合成方法与实施例13相同,仅以2-氟-5-溴苯胺代替2-氟苯胺。
黄色固体,产率:60%;1H NMR(500MHz,DMSO-d6)δ:9.16(s,1H),8.67(d,J=9.2Hz,1H),8.60(d,J=8.7Hz,1H),8.12(dd,J=9.0,2.3Hz,2H),7.92-7.75(m,1H),7.58(dd,J=9.1,2.3Hz,1H),7.39(d,J=8.2Hz,1H).13C NMR(125MHz,DMSO-d6)δ:149.78,137.23,132.35,132.03,130.77,130.55,130.30,129.34,128.01,125.12,122.27,117.68,116.93,116.53,101.93.MS-ESI m/z:calcd for C15H8BrClN2[M+H]+:332.9559;found:332.9706.
实施例17:化合物E17的合成
合成方法与实施例13相同,仅以2,5-二氟苯胺代替2-氟苯胺。
黄色固体,产率:43%;1H NMR(500MHz,DMSO-d6)δ:9.17(s,1H),8.67(dd,J=9.3,4.7Hz,2H),8.12(d,J=2.2Hz,1H),7.78(dd,J=9.3,3.1Hz,1H),7.60-7.51(m,2H),7.37(s,1H).13C NMR(125MHz,DMSO-d6)δ:149.77,137.21(d,J=11.3Hz),130.64,130.52,130.07,127.82,126.89(d,J=2.1Hz),125.00,122.19,117.30(d,J=8.7Hz),116.77,116.75,116.62,115.95(d,J=22.2Hz),101.51.MS-ESI m/z:calcd for C15H8ClFN2[M+H]+:270.0360;found:271.0520.
实施例18:化合物E18的合成
合成方法与实施例13相同,仅以2-氟-4-甲氧基苯胺代替2-氟苯胺。
黄色固体,产率:38%;1HNMR(500MHz,DMSO-d6)δ:8.96(s,1H),8.61(d,J=9.1Hz,1H),8.08(d,J=2.2Hz,1H),7.92(d,J=2.6Hz,1H),7.90(d,J=8.8Hz,1H),7.52(dd,J=9.0,2.3Hz,1H),7.28(s,1H),7.14(dd,J=8.8,2.5Hz,1H),4.02(s,3H).13C NMR(125MHz,DMSO-d6)δ:160.30,145.37,131.77,130.96,130.83,130.50,130.46,130.17,127.76,124.39,121.80,117.04,111.62,100.38,100.28,56.37.MS-ESIm/z:calcd for C16H11ClN2O[M+H]+:283.0560;found:283.0693.
实施例19:化合物E19的合成
合成方法与实施例13相同,仅以5-氟吲哚-2-羧酸代替5-氯吲哚-2-羧酸。
黄色固体,产率:56%;1H NMR(500MHz,DMSO-d6)δ:9.10(s,1H),8.71(dd,J=9.4,4.3Hz,1H),8.65(d,J=8.3Hz,1H),7.97(dd,J=7.9,1.5Hz,1H),7.79(dd,J=9.3,2.7Hz,1H),7.75-7.68(m,1H),7.52(t,J=7.6Hz,1H),7.42(td,J=9.2,2.8Hz,1H),7.34(s,1H).13C NMR(125MHz,DMSO-d6)δ:158.69(d,J=238.8Hz),148.22,135.74,131.09,130.52,130.13,129.95(d,J=11.0Hz),129.87,129.18,125.01,117.05(d,J=9.4Hz),115.50,113.51(d,J=26.5Hz),107.20(d,J=23.2Hz),101.42(d,J=5.4Hz).MS-ESI m/z:calcdfor C15H9FN2[M+H]+:237.0750;found:237.0903.
实施例20:化合物E20的合成
合成方法与实施例13相同,仅以2,5-氟苯胺代替2-氟苯胺,5-氟吲哚-2-羧酸代替5-氯吲哚-2-羧酸。
黄色固体,产率:42%;1H NMR(500MHz,DMSO-d6)δ:9.11(s,1H),8.70-8.59(m,2H),7.77(dd,J=9.3,2.7Hz,1H),7.73(dd,J=9.2,3.0Hz,1H),7.51(td,J=8.6,3.1Hz,1H),7.40(td,J=9.2,2.7Hz,1H),7.34(s,1H).13C NMR(125MHz,DMSO-d6)δ:159.49,157.91,149.57,137.12(d,J=11.2Hz),130.82,129.77(d,J=11.0Hz),129.13,126.96,117.04(d,J=8.9Hz),116.78(d,J=9.4Hz),116.59,115.89(d,J=22.5Hz),113.85(d,J=26.6Hz),107.29(d,J=23.2Hz),101.89(d,J=5.4Hz).MS-ESI m/z:calcd for C15H8F2N2[M+H]+:255.0656;found:255.0822.
实施例21:化合物E21的合成
合成方法与实施例13相同,仅以2-氟-5-氯苯胺代替2-氟苯胺,5-氟吲哚-2-羧酸代替5-氯吲哚-2-羧酸。
黄色固体,产率:48%;1H NMR(500MHz,DMSO-d6)δ:9.12(s,1H),8.63(m,2H),7.95(d,J=2.6Hz,1H),7.80(dd,J=9.3,2.8Hz,1H),7.68(dd,J=8.9,2.7Hz,1H),7.43(td,J=9.2,2.8Hz,1H),7.37(s,1H).13C NMR(125MHz,DMSO-d6)δ:158.78(d,J=238.5Hz),149.66,136.88,130.82,129.97(d,J=10.8Hz),129.38,129.22,129.18,128.98,128.55,117.18,116.97(d,J=10.0Hz),113.96(d,J=26.6Hz),107.44(d,J=23.1Hz),102.30(d,J=5.4Hz).MS-ESI m/z:calcd for C15H8ClFN2[M+H]+:271.0360;found:271.0512.
实施例22:化合物E22的合成
合成方法与实施例13相同,仅以5-溴吲哚-2-羧酸代替5-氯吲哚-2-羧酸。
黄色固体,产率:62%;1H NMR(500MHz,DMSO-d6)δ:9.14(s,1H),8.77-8.57(m,2H),8.28(s,1H),7.98(d,J=8.0Hz,1H),7.73(t,J=7.6Hz,1H),7.67(d,J=8.9Hz,1H),7.59-7.46(m,1H),7.36(s,1H).13C NMR(125MHz,DMSO-d6)δ:148.46,135.82,130.96,130.86,130.60,130.56,130.07,129.92,127.23,125.24,125.22,117.38,115.82,100.95.MS-ESIm/z:calcd for C15H9BrN2[M+H]+:298.9949;found:299.0080.
实施例23:化合物E23的合成
合成方法与实施例13相同,仅以2,5-氟苯胺代替2-氟苯胺,5-溴吲哚-2-羧酸代替5-氯吲哚-2-羧酸。
黄色固体,产率:47%;1HNMR(500MHz,DMSO-d6)δ:9.15(s,1H),8.64(dd,J=9.2,5.1Hz,1H),8.60(d,J=9.1Hz,1H),8.25(d,J=2.0Hz,1H),7.76(dd,J=9.3,3.1Hz,1H),7.65(dd,J=9.2,2.1Hz,1H),7.54(td,J=8.6,3.1Hz,1H),7.35(s,1H).13C NMR(125MHz,DMSO-d6)δ:158.81(d,J=242.0Hz),149.84,137.21(d,J=11.4Hz),130.85,130.48(d,J=42.3Hz),127.52,126.89(d,J=2.2Hz),125.39,117.39(d,J=9.3Hz),117.10,116.75(d,J=23.3Hz),116.09,115.94,115.91,101.43.MS-ESI m/z:calcd for C15H8BrFN2[M+H]+:316.9855;found:316.9966.
实施例24:化合物E24的合成
合成方法与实施例13相同,仅以2-氟-5-氯苯胺代替2-氟苯胺,5-溴吲哚-2-羧酸代替5-氯吲哚-2-羧酸。
黄色固体,产率:57%;1H NMR(500MHz,DMSO-d6)δ:9.10(s,1H),8.57(d,J=9.0Hz,1H),8.54(d,J=9.1Hz,1H),8.21(d,J=2.0Hz,1H),7.92(d,J=2.5Hz,1H),7.66(dd,J=9.1,2.4Hz,1H),7.62(d,J=9.1Hz,1H),7.33(s,1H).13C NMR(125MHz,DMSO-d6)δ:149.83,130.85,130.36,129.43,129.41,129.24,129.21,127.60,125.42,117.48,117.43,117.21,116.09,113.62,101.78.MS-ESI m/z:calcd for C15H8BrClN2[M+H]+:332.9559;found:332.9691.
实施例25:化合物E25的合成
合成方法与实施例13相同,仅以6-溴吲哚-2-羧酸代替5-氯吲哚-2-羧酸。
黄色固体,产率:61%;1HNMR(500MHz,DMSO-d6)δ:9.10(s,1H),8.85(s,1H),8.64(d,J=8.1Hz,1H),7.99(d,J=8.6Hz,1H),7.97-7.91(m,1H),7.72(t,J=7.8Hz,1H),7.61(dd,J=9.1,4.2Hz,1H),7.53(t,J=7.6Hz,1H),7.38(s,1H).13CNMR(125MHz,DMSO-d6)δ:148.55,135.88,132.72,130.44,130.28,130.04,129.95,127.96,126.39,125.25,124.81,117.84,117.65,116.12,101.78.MS-ESI m/z:calcd for C15H9BrN2[M+H]+:298.9949;found:299.0081.
实施例26:化合物E26的合成
合成方法与实施例13相同,仅以2-氟-5-氯苯胺代替2-氟苯胺,6-溴吲哚-2-羧酸代替5-氯吲哚-2-羧酸。
黄色固体,产率:52%;1H NMR(500MHz,DMSO-d6)δ:9.15(s,1H),8.84(s,1H),8.73-8.65(m,1H),8.02(d,J=8.6Hz,1H),7.97(d,J=2.7Hz,1H),7.70(td,J=8.5,2.8Hz,1H),7.64(d,J=8.1Hz,1H),7.44(d,J=3.5Hz,1H).13C NMR(125MHz,DMSO-d6)δ:149.94,137.07,132.74,130.02,129.28,129.20,128.91,128.77,127.94,126.61,124.95,118.25,117.77,117.54,102.60.MS-ESI m/z:calcd for C15H8BrClN2[M+H]+:332.9559;found:332.9682.
实施例27:化合物E27的合成
合成方法与实施例13相同,仅以2-氟-5-三氟甲基苯胺代替2-氟苯胺,6-溴吲哚-2-羧酸代替5-氯吲哚-2-羧酸。
黄色固体,产率:58%;1H NMR(500MHz,DMSO-d6)δ:9.14(d,J=1.6Hz,1H),8.80(s,1H),8.76(d,J=8.7Hz,1H),8.15(d,J=2.3Hz,1H),7.98(dd,J=8.6,1.8Hz,1H),7.91(d,J=8.6Hz,1H),7.62(d,J=8.6Hz,1H),7.42(s,1H).13C NMR(125MHz,DMSO-d6)δ:150.30,135.81,132.97,132.70,130.14,128.18,126.97,126.94,126.91,125.93,125.90,125.04,118.58,117.69,117.22,103.29.MS-ESI m/z:calcd for C16H8BrF3N2[M+H]+:366.9823;found:366.9962.
实施例28:化合物E28的合成
合成方法与实施例13相同,仅以5-甲氧基吲哚-2-羧酸代替5-氯吲哚-2-羧酸。
黄色固体,产率:43%;1H NMR(500MHz,DMSO-d6)δ:8.99(s,1H),8.61(d,J=8.4Hz,1H),8.00-7.87(m,3H),7.69(t,J=7.5Hz,1H),7.49(t,J=7.5Hz,1H),7.30(s,1H),7.22-7.13(m,1H),4.01(s,3H).13C NMR(125MHz,DMSO-d6)δ:158.19,148.55,136.08,133.17,130.52,130.12,129.39,129.31,124.74,124.02,123.46,115.80,114.39,101.92,97.71,56.30.MS-ESI m/z:calcd for C16H12N2O[M+H]+:249.0950;found:249.1123.
实施例29:化合物E29的合成
合成方法与实施例13相同,仅以6-甲氧基吲哚-2-羧酸代替5-氯吲哚-2-羧酸。
黄色固体,产率:41%;1HNMR(500MHz,DMSO-d6)δ:9.06(s,1H),8.61(dd,J=8.4,1.2Hz,1H),8.58(d,J=9.3Hz,1H),7.95(dd,J=7.9,1.6Hz,1H),7.70(m,1H),7.52-7.45(m,2H),7.27(s,1H),7.20(dd,J=9.3,2.6Hz,1H),3.89(s,3H).13C NMR(125MHz,DMSO-d6)δ:155.83,148.04,135.74,130.38,130.31,130.28,129.61,127.64,124.58,116.36,116.06,115.37,102.99,101.06,55.80.MS-ESI m/z:calcd for C16H12N2O[M+H]+:249.0950;found:249.1106.
实施例30:小檗碱类似物对植物病原真菌的抑菌活性测定及结果
1)供试药剂:化合物E1~E29。
2)供试菌种:立枯丝核菌、油菜菌核病菌、番茄灰霉病菌、小麦赤霉病菌、稻瘟病菌和辣椒疫霉病菌由甘肃省农业科学院提供。
3)抗菌活性测试:
测试方法:抗菌活性测定采用马铃薯葡萄糖琼脂培养基(PDA培养基)进行。其制备方法如下:先将马铃薯洗净去皮,称取200g切成小块,加水煮烂(煮沸20-30分钟,马铃薯块能被玻璃棒戳破即可),用八层纱布过滤,加热,再加15g琼脂,继续加热搅拌混匀,待琼脂溶解完后,加入葡萄糖,搅拌均匀,稍冷却后再补足水分至1000毫升,分装锥形瓶,加塞、包扎,115℃灭菌2h,备用。将化合物E1~E29分别用DMSO溶解,加入培养基中,混合均匀,使培养基中的化合物浓度分别为50μg/mL,以等浓度的DMSO作为空白对照,以上市药物嘧菌酯为阳性对照。倒平板,冷却后分别接菌,置于23摄氏度培养箱中培养,以空白对照菌丝长满培养皿为限,测定各化合物的抑菌率。所有试验设三个平行组或重复三次。抑菌率的计算按下述计算公式进行:
所测得目标化合物抗植物病原真菌活性结果见表1和表2。
表1 50μg/mL下目标化合物对植物病原真菌的抗菌作用
由表1活性测试结果可知,本发明制备的小檗碱类似物E1~E29对种植物病原真菌的表现出不同程度的抑制活性,为进一步探究其抗菌活性,部分高活性化合物在更低浓度下进行了抗菌活性测试,并计算了其EC50值。
表2高活性化合物对植物病原真菌的EC50值(μg/mL)
由表2活性测试结果可知,本发明制备的小檗碱类似物对6种植物病原真菌的表现出不同程度的抑制活性,其中化合物E19,E20和E21对立枯丝核菌表现出强效的抗菌活性,EC50值分别为0.098、0.065和0.073μg/mL,优于阳性对照药嘧菌酯,与立枯丝核菌特异性抗菌对照药噻呋酰胺相当。由此可见,本发明所述的小檗碱类似物结构简单、易于合成,具有进一步研究的价值,因而本发明所述的化合物可用于制备抗植物病原真菌的抗菌剂。
实施例31:小檗碱类似物对植物病原细菌的抑菌活性测定及结果
1)供试药剂:化合物E1~E29。
2)供试菌种:水稻白叶枯ACCC 11602,柑橘溃疡病菌和马铃薯黑胫菌ACCC 19901。
3)抗菌活性测试:
测试方法:抗菌活性测定采用牛肉膏蛋白胨培养基(NB培养基)进行。其制备方法如下:称取蛋白胨10g、牛肉膏3g和氯化钠5g,加入到1L蒸馏水中,并加热搅拌直到完全溶解,然后在121℃条件下通过高压蒸汽灭菌20-30分钟。灭菌完毕后,将其冷却至室温并分装至灭菌后的培养皿中,最后置于4℃冰箱中保存,备用。选取培养出来的细菌单菌转移至NB液体培养基中,然后通过恒温摇床在37℃,180rpm条件下的进行振荡培养直到对数生长期。接着,将处于对数生长期的细菌加入到NB液体培养基中并稀释至约1×106CFU/mL,备用。将化合物E1~E29用DMSO溶解,并加入到NB液体培养基中,混合均匀后制得药物浓度为200μg/mL的NB液体培养基。然后,取50μL上述制得的培养基和相同体积的含约1×106CFU/mL细菌的培养基加入到96孔板中,使其最终给药浓度变为100μg/mL。同时配置含有等量DMSO的100μL菌液做空白对照。将含有上述菌液的96孔板放在37℃的恒温培养箱中培养24小时,通过酶标仪测定孔中菌液的OD值(OD600)。此外,以测定的100μLNB液体培养基和浓度为100μg/mL药剂的OD值为基准对培养基和药剂本身造成的OD值进行矫正。校正OD值和抑制率的计算公式如下:
校正OD值=含菌培养基OD值-无菌培养物OD值;
抑制率=(校正后对照培养基菌液OD值-校正后含药培养基OD值)/校正后对照培养基菌液OD值×100%
所测得目标化合物抗植物病原细菌活性结果碱表3。
表3 100μg/mL下目标化合物对植物病原细菌的抗菌作用
由表3活性测试结果可知,本发明制备的小檗碱类似物E1~E29对3种植物病原细菌的表现出不同程度的抑制活性,其中化合物E3和E22在100μg/mL对马铃薯黑胫菌ACCC19901的抑制作用分别为80.41%和75.07,与对照药噻菌铜相当。本发明所述的小檗碱类似物结构简单,易于合成,具有进一步研究的价值,因而本发明所述的化合物可用于制备抗植物病原细菌的抗菌剂。
以上述依据本发明的理想实施例为启示,通过上述的说明内容,相关工作人员完全可以在不偏离本项发明技术思想的范围内,进行多样的变更以及修改。本项发明的技术性范围并不局限于说明书上的内容,必须要根据权利要求范围来确定其技术性范围。
Claims (8)
1.一种骨架跃迁型小檗碱类似物,其特征在于,所述小檗碱类似物的化学结构式为:
。
2.一种如权利要求1所述骨架跃迁型小檗碱类似物在制备防治或抗立枯丝核菌的药物中的应用。
3.一种如权利要求1所述骨架跃迁型小檗碱类似物在制备防治或抗油菜菌核病菌的药物中的应用。
4.一种如权利要求1所述骨架跃迁型小檗碱类似物在制备防治或抗番茄灰霉病菌的药物中的应用。
5.一种如权利要求1所述骨架跃迁型小檗碱类似物在制备防治或抗小麦赤霉病菌的药物中的应用。
6.一种如权利要求1所述骨架跃迁型小檗碱类似物在制备防治或抗稻瘟病菌的药物中的应用。
7.一种如权利要求1所述骨架跃迁型小檗碱类似物在制备防治或抗辣椒疫霉病的药物中的应用。
8.一种如权利要求1所述骨架跃迁型小檗碱类似物在制备防治或抗水稻白叶枯ACCC11602、柑橘溃疡病菌和马铃薯黑胫菌ACCC 19901植物病原细菌的药物中的应用。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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CN112106779A (zh) * | 2019-06-20 | 2020-12-22 | 兰州大学 | 一种a环修饰的白叶藤碱衍生物在防治农业植物病害中的应用 |
CN112457339A (zh) * | 2020-12-23 | 2021-03-09 | 上海应用技术大学 | 一种吡咯[1,2-a]喹喔啉衍生物的合成方法 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103333171A (zh) * | 2013-06-17 | 2013-10-02 | 南京工业大学 | 吡咯[1,2-a]喹喔啉衍生物的合成方法 |
CN112106779A (zh) * | 2019-06-20 | 2020-12-22 | 兰州大学 | 一种a环修饰的白叶藤碱衍生物在防治农业植物病害中的应用 |
CN112457339A (zh) * | 2020-12-23 | 2021-03-09 | 上海应用技术大学 | 一种吡咯[1,2-a]喹喔啉衍生物的合成方法 |
Non-Patent Citations (1)
Title |
---|
Transition-metal-free N-arylation: A general approach to aza-fused poly-heteroaromatics;Srikanth Annareddygari et al.;《J Heterocyclic Chem.》;第1-10页 * |
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