CN115918662A - 一种3-芳基异喹啉类小檗碱简化衍生物在防治农业病真菌中的用途 - Google Patents
一种3-芳基异喹啉类小檗碱简化衍生物在防治农业病真菌中的用途 Download PDFInfo
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Abstract
本发明公开一种3‑芳基异喹啉类小檗碱简化衍生物在防治农业病真菌中的用途。通过生物活性测试可知，该类衍生物对核盘菌、立枯丝核病菌、番茄灰霉病菌、小麦赤霉病菌、辣椒疫霉病菌以及稻瘟病菌等6种植物病害表现出一定的抑制活性，其中对立枯丝核病菌具有较好的抑制效果。本发明所涉及化合物制备难度低，原料廉价易得，有望开发为一种新型农业抗菌剂。
Description
技术领域
本发明属于天然药物化学领域，公开了一种3-芳基异喹啉衍生物的新用途，具体涉及化合物YKL-1～YKL-47在防治由核盘菌Sclerotinia sclerotiorum、立枯丝核病菌Rhizoctonia solani、禾谷镰刀菌Fusarium graminearum、番茄灰霉Botrytis cinerea、稻瘟病菌Magnaporthegrisea及辣椒疫霉菌Phytophthora capsici Leonian 引起的植物病害中的用途。
背景技术
植物病原真菌是危害最大的植物病原微生物之一，不仅可以造成巨大的经济损失，而且还会造成严重的植物疾病以及农作物的减产，甚至危害人类健康和生态环境。目前人们主要通过化学农药来控制植物真菌感染，但长期不合理的使用导致真菌对药物的耐药性迅速增加、环境污染以及残留物毒性等问题不断出现。因此，急需积极探索出具有新型抗植物病原菌药物成为现阶段急需解决的问题。
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。天然产物结构简化是一种在保留其药理活性的同时将复杂化学结构简化成为基本化学结构的策略。相比于原本较为复杂的化学结构，简化后的衍生物可能表现出更强或者更加广泛的生物活性，还可以改善它们的药物动力学特性，减少副作用。本研究表明，小檗碱简化衍生物对多种病原菌都表现出较强的抗菌活性，优于小檗碱。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较好的开发潜力。
因此，我们通过对小檗碱结构进行简化改造，得到一系列3-芳基异喹啉衍生物结构，并对其进行了抗植物病原真菌活性测试。测试结果表明，本发明所述的异喹啉衍生物对油菜菌核盘菌Sclerotinia sclerotiorum、立枯丝核病菌Rhizoctonia solani、禾谷镰刀菌Fusarium graminearum、番茄灰霉Botrytis cinerea、稻瘟病菌 Magnaporthegrisea及辣椒疫霉菌Phytophthora capsici Leonian具有显著的抗菌活性，具有进一步开发其成为新型农用杀菌剂的潜力。
发明内容
本发明的目的是提供一种3-芳基异喹啉衍生物，用于防治核盘菌Sclerotiniasclerotiorum、立枯丝核病菌Rhizoctonia solani、禾谷镰刀菌Fusarium graminearum、番茄灰霉Botrytis cinerea、稻瘟病菌Magnaporthegrisea及辣椒疫霉菌 Phytophthoracapsici Leonian引起的植物病害。
为实现上述目的，本发明提供了如下技术方法：
基于不同结构的异喹啉衍生物对核盘菌Sclerotinia sclerotiorum、立枯丝核病菌Rhizoctonia solani、禾谷镰刀菌Fusarium graminearum、番茄灰霉Botrytis cinerea、稻瘟病菌Magnaporthegrisea及辣椒疫霉菌Phytophthora capsici Leonian 的抑制作用。
本发明提供的3-芳基异喹啉衍生物作为新型杀菌剂，具有以下优势：
1)本发明所涉及的3-芳基异喹啉衍生物对农业病原真菌表现优异的抗菌活，化合物YKL-46对于立枯丝核菌表现出最强的抗菌活性，其EC50值为5.550μg/mL。此外，YKL-46对于其它5种测试真菌也表现出较好的抗菌作用，EC50值在 9.281～30.920μg/mL之间。
2)本发明的3-芳基异喹啉衍生物，具有结构简单、易于合成、原药价格便宜等优点，有望开发为新型杀菌剂。
具体实施方式
为了更好地理解本发明，通过以下具体实施例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1：3-苯基异喹啉衍生物YKL-1～YKL-17的合成
3-苯基异喹啉小檗碱类似物YKL-1～YKL-17的合成路线按如下反应式进行：
将3-溴异喹啉(3mmol)加入到3mL乙醇、6mL水和12mL甲苯的混合溶液中，搅拌均匀后再在室温下加入不同取代的苯硼酸(4.5mmol)，适量的K2CO3 (12mmol)和Pd(PPh3)4(0.150mmol)。反应混合物在氩气保护下95℃加热搅拌12小时，待完毕后将反应混合物冷却至室温，并用饱和NH4Cl溶液淬灭反应，用二氯甲烷萃取三次。合并的有机层，在真空中浓缩，并通过柱色谱纯化，最终得到3-苯基异喹啉小檗碱类似物YKL-1～YKL-17。(合成方法参见文献： Chemical Science,2016,7(12):6940-6945.)
实施例2：3-苯基异喹啉衍生物YKL-18～YKL-33的合成
3-苯基异喹啉小檗碱类似物YKL-18～YKL-33的合成路线按如下反应式进行：
将不同取代的2-溴苯甲醛(1mmol)、不同取代的苯乙炔(1.2mmol)和叔丁胺(4.5mmol)加入到10mL DMF溶液中，再加入PdCl2(0.05mmol)、PPh3 (0.15mmol)和CuI(0.05mmol)。将所得反应混合物在100℃下加热8-14h，通过TLC监测反应，直到原料完全消耗后，将反应液冷却至室温。旋干反应液，用乙酸乙酯和水稀释并萃取反应混合物三次，合并乙酸乙酯层，然后在真空中浓缩。所得粗品经柱色谱纯化后得到3-苯基异喹啉小檗碱类似物YKL-18～YKL-33。 (合成方法参见文献：Organic&Biomolecular Chemistry,2016,14(38): 9063-9071.)
实施例3：3-芳基异喹啉衍生物YKL-34～YKL-47的合成
3-芳基异喹啉小檗碱类似物YKL-34～YKL-47的合成路线按如下反应式进行：
将3-溴异喹啉(3mmol)加入到3mL乙醇、6mL水和12mL甲苯的混合溶液中，然后加入不同芳环取代硼酸类化合物(4.5mmol)，适量的K2CO3(12mmol) 和Pd(PPh3)4(0.150mmol)。在氩气保护的作用下，反应液在95℃加热搅拌 12小时，完毕后，将反应液冷却至室温，并用饱和NH4Cl溶液停止反应进程，用二氯甲烷萃取三次。合并的二氯甲烷层并在真空中浓缩，所得粗产物通过柱色谱纯化，最终得到3-芳基异喹啉小檗碱类似物YKL-34～YKL-47。(合成方法参见文献：Chemical Science,2016,7(12):6940-6945.)
实施例4：化合物YKL-1～YKL-47的物理性质及结构表征
化合物YKL-1
白色固体，产率：85％；1H NMR(500MHz,Chloroform-d)δ:9.34(d,J＝3.6Hz, 1H),8.17-8.09(m,2H),8.07(s,1H),8.01-7.93(m,1H),7.87(d,J＝8.2Hz,1H), 7.69(t,J＝8.2Hz,1H),7.58(t,J＝8.1Hz,1H),7.51(dd,J＝8.4,7.0Hz,2H),7.46- 7.36(m,1H).13CNMR(125MHz,Chloroform-d)δ:152.39,151.26,139.54,136.71, 130.60,128.83,128.57,127.77,127.61,127.12,127.04,126.94,116.58.MS-ESI m/z: calcd for C15H11N[M+H]+:206.0891；found:206.0944.
化合物YKL-2
白色固体，产率：89％；1H NMR(500MHz,Chloroform-d)δ:9.32(s,1H),8.17 -8.08(m,2H),8.01(s,1H),7.98(d,J＝8.2Hz,1H),7.86(d,J＝8.2Hz,1H),7.73- 7.66(m,1H),7.63-7.55(m,1H),7.22-7.15(m,2H).13C NMR(125MHz, Chloroform-d)δ:163.31(d,J＝247.5Hz),152.41,150.28,136.68,135.70(d,J＝3.1 Hz),130.71,128.76(d,J＝8.3Hz),127.67,127.62,127.17,126.87,116.23,115.70 (d,J＝21.3Hz).MS-ESI m/z:calcd forC15H10FN[M+H]+:224.0797；found: 224.0850.
化合物YKL-3
白色固体，产率：87％；1H NMR(500MHz,Chloroform-d)δ:9.29(s,1H),8.03 -7.92(m,2H),7.83(d,J＝8.2Hz,1H),7.71-7.62(m,3H),7.56(t,J＝7.5Hz,1H), 6.94(d,J＝7.9Hz,1H),6.03(s,2H).13C NMR(125MHz,Chloroform-d)δ:151.17, 149.80,147.30,147.10,135.71,132.98,129.53,126.55,126.52,125.83,125.77, 119.94,114.70,107.53,106.44,100.24.MS-ESI m/z:calcd for C16H11NO2[M+H]+: 250.0790；found:250.0841.
化合物YKL-4
白色固体，产率：87％；1H NMR(500MHz,Chloroform-d)δ:9.24(s,1H),7.93 (s,1H),7.92-7.88(m,1H),7.78(d,J＝8.2Hz,1H),7.70(d,J＝2.1Hz,1H),7.65- 7.56(m,2H),7.50-7.48(m,1H),6.92(d,J＝8.4Hz,1H),3.96(s,3H),3.88(s,3H). 13C NMR(125MHz,Chloroform-d)δ:151.13,149.87,148.65,148.29,135.76, 131.44,129.57,126.59,126.47,125.79,125.74,118.37,114.64,110.25,109.12, 55.01,54.97.MS-ESI m/z:calcd for C17H15NO2[M+H]+:266.1103；found:266.1151.
化合物YKL-5
白色固体，产率：92％；1H NMR(500MHz,Chloroform-d)δ:9.33(s,1H),8.06 (s,1H),8.00(d,J＝8.2Hz,1H),7.93-7.83(m,3H),7.75-7.68(m,1H),7.64-7.57 (m,1H),7.50-7.39(m,1H),7.11-7.09(m,1H).13C NMR(125MHz,Chloroform-d) δ:162.40(d,J＝245.4Hz),151.44,148.80(d,J＝2.8Hz),140.86(d,J＝7.7Hz), 135.52,129.71,129.20(d,J＝8.3Hz),126.97,126.59,126.42,125.97,121.42(d,J＝ 2.8Hz),115.80,114.30(d,J＝21.3Hz),112.91(d,J＝22.8Hz).MS-ESI m/z:calcd for C15H10FN[M+H]+:224.0797；found:224.0851.
化合物YKL-6
白色固体，产率：83％；1H NMR(500MHz,Chloroform-d)δ:9.31(s,1H),8.05 -7.94(m,3H),7.89-7.79(m,2H),7.76-7.67(m,1H),7.61(t,J＝7.6Hz,1H),7.34 -7.18(m,1H).13C NMR(125MHz,Chloroform-d)δ:152.51,151.76(d,J＝12.9 Hz),149.77(d,J＝12.8Hz),148.98,136.90-136.59(m),130.8,127.89,127.64, 127.50,126.94,122.81(dd,J＝6.3,3.6Hz),117.49(d,J＝17.4Hz),116.44,116.03 (d,J＝18.5Hz).MS-ESI m/z:calcd for C15H9F2N[M+H]+:242.0703；found: 242.0754.
化合物YKL-7
白色固体，产率：88％；1H NMR(500MHz,Chloroform-d)δ:9.32(s,1H),8.03 (d,J＝1.6Hz,2H),8.02(s,1H),7.97(dd,J＝8.2,1.1Hz,1H),7.85(dd,J＝8.3,1.0 Hz,1H),7.71-7.60(m,1H),7.59-7.52(m,1H),7.31(d,J＝7.9Hz,2H),2.42(s, 3H).13C NMR(125MHz,Chloroform-d)δ:152.31,151.30,138.51,136.76,136.73, 130.52,129.57,127.65,127.60,126.90,126.88,116.06,21.29.MS-ESI m/z:calcd for C16H13N[M+H]+:220.1048；found:220.1102.
化合物YKL-8
白色固体，产率：85％；1H NMR(500MHz,Chloroform-d)δ:9.33(s,1H),8.15 (t,J＝1.9Hz,1H),8.05(s,1H),8.03-7.98(m,2H),7.88(d,J＝8.2Hz,1H),7.76- 7.68(m,1H),7.65-7.57(m,1H),7.43(t,J＝7.8Hz,1H),7.38(dt,J＝8.0,1.5Hz, 1H).13C NMR(125MHz,Chloroform-d)δ:152.51,149.70,141.35,136.57,134.92, 130.80,130.03,128.53,127.99,127.64,127.51,127.17,127.01,125.03,116.90. MS-ESI m/z:calcd forC15H10ClN[M+H]+:240.0502；found:240.0555.
化合物YKL-9
白色固体，产率：83％；1H NMR(500MHz,Chloroform-d)δ:9.29(s,1H),8.07 (d,J＝8.8Hz,2H),7.97(s,1H),7.95(d,J＝7.8Hz,1H),7.82(d,J＝8.3Hz,1H), 7.65(t,J＝6.9Hz,1H),7.53(t,J＝6.9Hz,1H),7.03(d,J＝8.8Hz,2H),3.87(s,3H). 13C NMR(125MHz,Chloroform-d)δ:160.18,152.31,151.08,136.80,132.25, 130.49,128.26,127.59,127.46,126.77,126.71,115.47,114.23,55.39.MS-ESI m/z: calcd for C16H13NO[M+H]+:236.0997；found:236.1065.
化合物YKL-10
白色固体，产率：87％；1H NMR(500MHz,Chloroform-d)δ:9.33(s,1H),8.05 (d,J＝1.1Hz,1H),7.98(dd,J＝8.2,1.1Hz,1H),7.90-7.82(m,1H),7.72(dd,J＝ 2.6,1.7Hz,1H),7.72-7.65(m,2H),7.61-7.53(m,1H),7.41(t,J＝7.9Hz,1H), 6.97(dd,J＝8.2,1.7Hz,1H),3.92(s,3H).13C NMR(125MHz,Chloroform-d)δ: 160.15,152.33,151.06,141.08,136.62,130.55,129.76,127.84,127.56,127.12, 126.94,119.40,116.74,114.63,112.19,55.40.MS-ESI m/z:calcd for C16H13NO [M+H]+:236.0997；found:236.1067.
化合物YKL-11
白色固体，产率：88％；1H NMR(500MHz,Chloroform-d)δ:9.34(s,1H),8.20 (s,1H),7.97(d,J＝7.1Hz,1H),7.92(dd,J＝7.6,1.8Hz,1H),7.85(dd,J＝8.3,1.0 Hz,1H),7.70-7.63(m,1H),7.61-7.55(m,1H),7.41-7.34(m,1H),7.13-7.11(m, 1.1Hz,1H),7.04(d,J＝8.3Hz,0H),3.89(s,3H).13C NMR(125MHz, Chloroform-d)δ:157.09,151.91,149.31,136.18,131.46,130.18,129.48,129.20, 127.40,127.39,127.02,126.94,121.10,121.05,111.47,55.71.MS-ESI m/z:calcd for C16H13NO[M+H]+:236.0997；found:236.1065.
化合物YKL-12
白色固体，产率：81％；1H NMR(500MHz,Chloroform-d)δ:9.32(s,1H),8.04 (s,1H),7.98(d,J＝8.1Hz,1H),7.86(d,J＝8.2Hz,1H),7.69(t,J＝7.0Hz,1H), 7.58(t,J＝7.0Hz,1H),7.30(d,J＝2.3Hz,2H),6.54(t,J＝2.3Hz,1H),3.90(s,6H). 13C NMR(125MHz,Chloroform-d)δ:161.22,152.25,151.01,141.74,136.63, 130.62,127.94,127.59,127.21,126.99,116.91,105.06,101.12,55.55.MS-ESI m/z: calcd for C17H15NO2[M+H]+:266.1103；found:266.1172.
化合物YKL-13
白色固体，产率：89％；1H NMR(500MHz,Chloroform-d)δ:9.36(s,1H),8.22 (d,J＝8.4Hz,2H),8.11(s,1H),8.00(d,J＝8.1Hz,1H),7.88(d,J＝8.2Hz,1H), 7.78-7.74(m,2H),7.71-7.66(m,3H),7.59(t,J＝7.5Hz,1H),7.47(t,J＝7.7Hz, 2H),7.37(t,J＝7.4Hz,1H).13C NMR(125MHz,Chloroform-d)δ:152.49,150.87, 141.29,140.72,138.50,136.70,130.60,128.85,127.83,127.63,127.53,127.48, 127.39,127.12,126.96,116.41.MS-ESIm/z:calcd for C21H15N[M+H]+:282.1204； found:282.1273.
化合物YKL-14
白色固体，产率：84％；1H NMR(500MHz,Chloroform-d)δ:9.32(s,1H),8.07 (dd,J＝8.5,1.3Hz,2H),8.03(s,1H),7.99(d,J＝8.2Hz,1H),7.86(dd,J＝8.4,2.0 Hz,1H),7.70(t,J＝7.6Hz,1H),7.63-7.56(m,1H),7.47(d,J＝8.5Hz,2H).13C NMR(125MHz,Chloroform-d)δ:152.51,150.05,138.03,136.60,134.62,130.72, 128.97,128.25,127.85,127.62,127.33,126.93,116.47.MS-ESI m/z:calcd for C15H10ClN[M+H]+:240.0502；found:240.0580.
化合物YKL-15
白色固体，产率：83％；1H NMR(500MHz,Chloroform-d)δ:9.30(s,1H),8.05 (d,J＝8.3Hz,2H),8.01(s,1H),7.95(d,J＝8.1Hz,1H),7.83(d,J＝8.3Hz,1H), 7.67(t,J＝7.5Hz,1H),7.60-7.51(m,1H),7.37(d,J＝8.2Hz,2H),2.53(s,3H).13C NMR(125MHz,Chloroform-d)δ:152.42,150.69,139.24,136.69,136.31,130.60, 127.72,127.61,127.31,127.02,126.88,126.63,116.01,15.69.MS-ESI m/z:calcd for C16H13NS[M+H]+:252.0769；found:252.0843.
化合物YKL-16
白色固体，产率：91％；1H NMR(500MHz,Chloroform-d)δ:9.36(s,1H),8.34 (d,J＝8.5Hz,2H),8.16(s,1H),8.07(d,J＝8.5Hz,2H),8.03(d,J＝8.1Hz,1H), 7.92(d,J＝8.1Hz,1H),7.75(t,J＝7.6Hz,1H),7.66(t,J＝7.5Hz,1H),3.11(s,3H). 13C NMR(125MHz,Chloroform-d)δ:152.83,148.92,144.83,140.02,136.37, 131.00,128.28,128.05,127.89,127.76,127.67,127.18,117.85,44.65.MS-ESI m/z: calcd for C16H13NO2S[M+H]+:284.0667；found:284.0741.
化合物YKL-17
黄色固体，产率：81％；1H NMR(500MHz,Chloroform-d)δ:9.36(s,1H),8.36 (t,J＝1.9Hz,1H),8.11(s,1H),8.09(d,J＝7.7Hz,1H),7.98(dd,J＝8.1,1.1Hz, 1H),7.90-7.83(m,1H),7.73-7.67(m,2H),7.67-7.61(m,1H),7.60-7.54(m,2H), 7.46(t,J＝7.7Hz,3H),7.39-7.34(m,1H).13C NMR(125MHz,Chloroform-d)δ: 151.40,150.17,140.80,140.14,139.00,135.63,129.60,128.21,127.72,127.59, 126.78,126.57,126.28,126.14,126.03,125.90,124.98,124.94,115.80.MS-ESI m/z: calcd for C21H15N[M+H]+:282.1204；found:282.1280.
化合物YKL-18
白色固体，产率：86％；1H NMR(500MHz,Chloroform-d)δ:9.13(s,1H),8.14 -8.04(m,2H),7.93(s,1H),7.49(t,J＝7.6Hz,2H),7.42-7.36(m,1H),7.22(s,1H), 7.12(s,1H),4.05(s,3H),4.04(s,3H).13C NMR(125MHz,Chloroform-d)δ:152.22, 149.33,149.19,148.75,138.81,132.39,127.72,127.19,125.75,122.75,114.54, 104.26,103.95,55.10,55.06.MS-ESI m/z:calcd for C17H15NO2[M+H]+:266.1103； found:266.1153.
化合物YKL-19
黄色固体，产率：68％；1H NMR(500MHz,Chloroform-d)δ:9.29(s,1H),8.11 (dd,J＝8.3,1.3Hz,2H),8.06(s,1H),7.88(dd,J＝9.0,5.2Hz,1H),7.59(dd,J＝8.7, 2.6Hz,1H),7.54-7.47(m,3H),7.44-7.40(m,1H).13C NMR(125MHz, Chloroform-d)δ:159.80(d,J＝249.8Hz),150.51(d,J＝5.5Hz),149.95(d,J＝3.5 Hz),138.20,132.70,129.40,128.54(d,J＝8.5Hz),127.82,127.61,127.19(d,J＝ 8.5Hz),125.88,120.24(d,J＝25.7Hz),115.26,109.68,109.51.MS-ESI m/z:calcd for C15H10FN[M+H]+:224.0797；found:224.0850.
化合物YKL-20
白色固体，产率：78％；1H NMR(500MHz,Chloroform-d)δ:9.30(s,1H),8.11 (dd,J＝7.1,1.5Hz,2H),8.03-7.97(m,2H),7.51(dd,J＝8.3,6.9Hz,2H),7.46(dd, J＝9.5,2.5Hz,1H),7.45-7.41(m,1H),7.35-7.33(m,1H).13C NMR(125MHz, Chloroform-d)δ:163.50(d,J＝252.2Hz),152.11,152.03,139.15,138.17(d,J＝ 10.9Hz),130.65,130.57,128.87,127.11,124.95,117.68(d,J＝25.7Hz),116.08(d, J＝5.5Hz),110.24(d,J＝20.6Hz).MS-ESI m/z:calcd for C15H10FN[M+H]+: 224.0797；found:224.0850.
化合物YKL-21
白色固体，产率：72％；1H NMR(500MHz,Chloroform-d)δ:9.19(d,J＝4.5Hz, 1H),8.14-8.05(m,2H),7.97(s,1H),7.87(d,J＝8.8Hz,1H),7.51-7.49(m,2H), 7.41(td,J＝7.1,1.4Hz,1H),7.22-7.20(m,1H),7.12(d,J＝2.4Hz,1H),3.96(d,J ＝1.5Hz,3H).13C NMR(125MHz,Chloroform-d)δ:160.17,150.67,150.43,138.63, 137.65,128.25,127.74,127.49,126.00,122.58,119.20,114.94,103.42,54.47. MS-ESI m/z:calcd for C16H13NO[M+H]+:236.0997；found:236.1051.
化合物YKL-22
白色固体，产率：79％；1H NMR(500MHz,Chloroform-d)δ:9.24(s,1H),8.14 -8.05(m,2H),8.00(s,1H),7.77(d,J＝8.9Hz,1H),7.50(t,J＝7.7Hz,2H),7.39(t, J＝7.4Hz,1H),7.35(dd,J＝8.9,2.5Hz,1H),7.24(d,J＝2.5Hz,1H),3.96(s,3H). 13C NMR(125MHz,Chloroform-d)δ:157.41,149.82,148.57,138.62,131.28, 127.85,127.75,127.45,127.20,125.72,122.82,115.43,103.68,54.49.MS-ESI m/z: calcd for C16H13NO[M+H]+:236.0997；found:236.1063.
化合物YKL-23
白色固体，产率：71％；1H NMR(500MHz,Chloroform-d)δ:9.44(s,1H),8.30 (s,1H),8.18-8.11(m,3H),7.99(d,J＝8.6Hz,1H),7.86(dd,J＝8.6,1.7Hz,1H), 7.53(dd,J＝8.4,6.9Hz,2H),7.50-7.42(m,1H).13C NMR(125MHz, Chloroform-d)δ:153.35,153.08,138.76,138.01,129.22,128.96,128.18,127.20, 126.43,126.23,126.21,126.18,125.62-125.44(m),116.15.MS-ESI m/z:calcd for C16H10F3N[M+H]+:274.0765；found:274.0831.
化合物YKL-24
白色固体，产率：68％；1H NMR(500MHz,Chloroform-d)δ:9.53(s,1H),8.95 (d,J＝2.4Hz,1H),8.46(dd,J＝9.0,2.3Hz,1H),8.18-8.16(m,3H),8.01(d,J＝ 9.0Hz,1H),7.60-7.52(m,2H),7.51-7.46(m,1H).13C NMR(125MHz, Chloroform-d)δ:154.78,154.10,145.94,139.18,138.29,129.69,129.04,128.75, 127.32,126.12,124.52,123.98,115.97.MS-ESI m/z:calcd for C15H10N2O2[M+H]+: 251.0742；found:251.0806.
化合物YKL-25
白色固体，产率：73％；1H NMR(500MHz,Chloroform-d)δ:9.26(s,1H),8.17 -8.06(m,2H),8.03(s,1H),7.96(d,J＝1.9Hz,1H),7.81(d,J＝8.7Hz,1H),7.62 (dd,J＝8.8,2.1Hz,1H),7.51(t,J＝7.7Hz,2H),7.47-7.39(m,1H).13C NMR(125 MHz,Chloroform-d)δ:151.71,151.37,139.12,134.95,132.59,131.61,128.89, 128.81,128.62,128.14,126.99,126.35,116.16.MS-ESI m/z:calcd for C15H10ClN [M+H]+:240.0502；found:240.0569.
化合物YKL-26
白色固体，产率：75％；1H NMR(500MHz,Chloroform-d)δ:9.28(s,1H),8.10 (dd,J＝8.7,5.5Hz,2H),8.00(dd,J＝8.9,5.5Hz,1H),7.96(s,1H),7.46(dd,J＝9.3, 2.4Hz,1H),7.36-7.34(m,1H),7.26(s,1H),7.19(t,J＝8.7Hz,2H).13C NMR(125 MHz,Chloroform-d)δ:164.52(d,J＝14.7Hz),162.53(d,J＝10.6Hz),152.03, 151.11,138.18(d,J＝11.1Hz),135.26,130.65(d,J＝9.5Hz),128.88(d,J＝8.3Hz), 124.86,117.77(d,J＝26.4Hz),115.78(d,J＝21.8Hz),115.74(d,J＝5.9Hz), 110.20(d,J＝21.1Hz).MS-ESI m/z:calcd for C15H9F2N[M+H]+:242.0703；found: 242.0769.
化合物YKL-27
白色固体，产率：68％；1H NMR(500MHz,Chloroform-d)δ:9.20(s,1H),8.08 -7.98(m,2H),7.93(s,1H),7.80(dd,J＝9.0,5.2Hz,1H),7.52(dd,J＝8.7,2.5Hz, 1H),7.42-7.40(m,1H),7.16-7.05(m,2H).13C NMR(125MHz,Chloroform-d)δ: 162.30(d,J＝248.2Hz),159.82(d,J＝249.3Hz),150.51(d,J＝5.5Hz),148.96(d, J＝3.3Hz),134.34(d,J＝3.5Hz),132.70,128.48(d,J＝8.3Hz),127.62(d,J＝8.3 Hz),127.11(d,J＝8.3Hz),120.38(d,J＝25.7Hz),114.94,114.72(d,J＝21.9Hz), 109.63(d,J＝20.4Hz).MS-ESI m/z:calcd for C15H9F2N[M+H]+:242.0703；found: 242.0771.
化合物YKL-28
白色固体，产率：65％；1H NMR(500MHz,Chloroform-d)δ:9.17(s,1H),8.00 (d,J＝8.0Hz,2H),7.93(s,1H),7.85(d,J＝8.9Hz,1H),7.31(d,J＝7.9Hz,2H), 7.18(dd,J＝8.9,2.4Hz,1H),7.09(d,J＝2.4Hz,1H),3.95(s,3H),2.42(s,3H).13C NMR(125MHz,Chloroform-d)δ:161.14,151.76,151.41,138.71,138.45,136.87, 126.88,123.52,120.03,115.49,104.38,55.49,21.29.MS-ESI m/z:calcd for C17H15NO[M+H]+:250.1154；found:250.1222.
化合物YKL-29
白色固体，产率：72％；1H NMR(500MHz,Chloroform-d)δ:9.16(d,J＝1.0Hz, 1H),8.08(dd,J＝8.8,5.4Hz,2H),7.90(s,1H),7.86(d,J＝8.9Hz,1H),7.22-7.14 (m,3H),7.10(d,J＝2.4Hz,1H),3.96(s,3H).13C NMR(125MHz,Chloroform-d)δ: 163.24(d,J＝247.4Hz),161.19,151.54,150.82,138.59,135.92(d,J＝2.9Hz), 129.23,128.71(d,J＝8.3Hz),123.52,120.20,115.69,115.53(d,J＝4.5Hz),104.37, 55.48.MS-ESI m/z:calcdfor C16H12FNO[M+H]+:254.0903；found:254.0970.
化合物YKL-30
白色固体，产率：71％；1H NMR(500MHz,Chloroform-d)δ:9.10(s,1H),8.07 -8.03(m,2H),7.87(s,1H),7.22(s,1H),7.17(t,J＝8.7Hz,2H),7.11(s,1H),4.05 (d,J＝1.5Hz,6H).13C NMR(125MHz,Chloroform-d)δ:163.09(d,J＝247.3Hz), 153.30,150.38,149.86,149.37,136.11(d,J＝3.5Hz),133.37,128.46(d,J＝7.6Hz), 123.71,115.68,115.50,115.22,105.09(d,J＝47.3Hz),56.13,56.10.MS-ESI m/z: calcd for C17H14FNO2[M+H]+:284.1009；found:284.1074.
化合物YKL-31
白色固体，产率：62％；1H NMR(500MHz,Chloroform-d)δ:9.10(s,1H),8.10 -7.98(m,2H),7.90(s,1H),7.61-7.34(m,2H),7.22(s,1H),7.11(s,1H),4.05(s, 6H).13C NMR(125MHz,Chloroform-d)δ:153.32,150.51,149.92,149.05,138.40, 134.20,133.31,128.88,127.99,123.91,115.42,105.30,104.96,56.14,56.11. MS-ESI m/z:calcd forC17H14ClNO2[M+H]+:300.0713；found:300.0778.
化合物YKL-32
白色固体，产率：69％；1H NMR(500MHz,Chloroform-d)δ:9.00(s,1H),7.95 (d,J＝8.5Hz,2H),7.76(s,1H),7.10(s,1H),6.99(s,1H),6.93(d,J＝8.5Hz,2H), 3.95(d,J＝1.9Hz,6H),3.78(s,3H).13C NMR(125MHz,Chloroform-d)δ:158.86, 152.10,149.03,149.02,148.70,132.42,131.58,126.90,122.38,113.47,113.09, 104.23,103.78,55.04,55.01,54.32.MS-ESI m/z:calcd for C18H17NO3[M+H]+: 296.1208；found:296.1276.
化合物YKL-33
白色固体，产率：63％；1H NMR(500MHz,Chloroform-d)δ:9.02(s,1H),7.90 (d,J＝7.9Hz,2H),7.81(s,1H),7.21(d,J＝7.8Hz,2H),7.11(s,1H),7.01(s,1H), 3.95(d,J＝1.3Hz,5H),2.33(s,3H).13C NMR(125MHz,Chloroform-d)δ:152.09, 149.30,149.14,148.73,137.01,136.09,132.35,128.43,125.57,122.62,114.03, 104.23,103.86,55.05,55.02,20.21.MS-ESI m/z:calcd for C18H17NO2[M+H]+: 280.1259；found:280.1328.
化合物YKL-34
白色固体，产率：85％；1H NMR(500MHz,Chloroform-d)δ:9.37(s,1H),8.64 (d,J＝1.8Hz,1H),8.23(dd,J＝8.6,1.8Hz,1H),8.18(s,1H),8.03-7.93(m,3H), 7.90-7.82(m,2H),7.68(t,J＝6.9Hz,1H),7.57(t,J＝6.9Hz,1H),7.54-7.45(m, 2H).13C NMR(125MHz,Chloroform-d)δ:151.47,150.05,135.75,135.66,132.66, 132.41,129.57,127.67,127.42,126.76,126.62,126.57,126.10,125.91,125.30, 125.24,123.64,115.82.MS-ESIm/z:calcd for C19H13N[M+H]+:256.1048；found: 256.1119.
化合物YKL-35
白色固体，产率：79％；1H NMR(500MHz,Chloroform-d)δ:9.42(s,1H),8.13 (d,J＝8.3Hz,1H),8.05(d,J＝7.1Hz,0H),7.93(s,2H),7.91(t,J＝1.0Hz,1H), 7.87(d,J＝8.2Hz,1H),7.72(t,J＝7.6Hz,1H),7.69(dd,J＝7.0,1.2Hz,1H),7.63 (t,J＝7.6Hz,1H),7.57(dd,J＝8.2,7.0Hz,1H),7.53-7.41(m,2H).13C NMR(125 MHz,Chloroform-d)δ:151.89151.11,137.65,135.34,132.97,130.51,129.56, 127.64,127.30,126.81,126.55,126.47,126.27,125.73,125.36,124.81,124.78, 124.32,120.13.MS-ESI m/z:calcd forC19H13N[M+H]+:256.1048；found:256.1117.
化合物YKL-36
白色固体，产率：69％；1H NMR(500MHz,Chloroform-d)δ:9.20(s,1H),8.04 (s,1H),8.01(s,1H),7.92(dd,J＝8.2,1.1Hz,1H),7.79-7.75(m,2H),7.64(t,J＝ 6.9Hz,1H),7.51(t,J＝7.0Hz,1H),3.97(s,3H).13C NMR(125MHz, Chloroform-d)δ:152.50,145.79,137.33,136.88,130.56,128.82,127.67,127.32, 126.37,126.31,123.92,114.47,39.16.MS-ESI m/z:calcd for C13H11N3[M+H]+: 210.0953；found:210.1022.
化合物YKL-37
白色固体，产率：81％；1H NMR(500MHz,Chloroform-d)δ:9.66(d,J＝2.3Hz, 1H),9.39(s,1H),8.92(d,J＝2.3Hz,1H),8.23(s,1H),8.17(d,J＝8.4Hz,1H),8.02 (d,J＝8.1Hz,1H),7.98-7.90(m,2H),7.77-7.70(m,2H),7.63(t,J＝7.5Hz,1H), 7.58(t,J＝7.0Hz,1H).13C NMR(125MHz,Chloroform-d)δ:152.97,149.43, 136.51,133.77,132.16,132.07,130.91,129.75,129.28,128.5,128.51,128.46, 128.08,127.69,127.67,127.04,127.00,117.09.MS-ESI m/z:calcd for C18H12N2 [M+H]+:257.1000；found:257.1069.
化合物YKL-38
白色固体，产率：76％；1H NMR(500MHz,Chloroform-d)δ:9.27(s,1H),8.23 (s,1H),7.96(d,J＝8.1Hz,1H),7.88(d,J＝8.3Hz,1H),7.69(t,J＝6.9Hz,1H), 7.65(d,J＝7.1Hz,1H),7.62-7.55(m,2H),7.50(s,1H),7.35-7.30(m,1H),7.29- 7.23(m,1H).13C NMR(125MHz,Chloroform-d)δ:155.76,155.32,152.83,143.04, 136.19,130.90,129.16,128.18,127.77,127.47,127.10,124.90,123.10,121.56, 115.85,111.31,104.56.MS-ESIm/z:calcd for C17H11NO[M+H]+:246.0841；found: 246.0909.
化合物YKL-39
白色固体，产率：81％；1H NMR(500MHz,Chloroform-d)δ:9.26(s,1H),9.25 (d,J＝2.4Hz,1H),8.57(dd,J＝4.8,1.6Hz,1H),8.36(d,J＝8.0Hz,1H),8.00(s, 1H),7.92(d,J＝8.1Hz,1H),7.81(d,J＝8.2Hz,1H),7.64(t,J＝7.6Hz,1H),7.54 (t,J＝7.6Hz,1H),7.34(dd,J＝8.0,4.7Hz,1H).13C NMR(125MHz,Chloroform-d) δ:151.81,148.45,147.49,147.32,135.40,134.09,133.33,129.80,126.97,126.59, 125.94,122.56,115.88.MS-ESIm/z:calcd for C14H10N2[M+H]+:207.0844；found: 207.0913.
化合物YKL-40
白色固体，产率：83％；1H NMR(500MHz,Chloroform-d)δ:9.21(s,1H),7.96 (s,1H),7.96-7.91(m,1H),7.80(d,J＝8.2Hz,1H),7.71-7.64(m,2H),7.53(t,J＝ 6.9Hz,1H),7.39(dd,J＝5.0,1.1Hz,1H),7.15(dd,J＝5.0,3.6Hz,1H).13C NMR (125MHz,Chloroform-d)δ:152.66,152.42,136.48,131.26,130.77,128.17,127.76, 127.67,126.85,126.66,125.63,123.88,114.30.MS-ESI m/z:calcd for C13H9NS [M+H]+:212.0456；found:212.0527.
化合物YKL-41
白色固体，产率：89％；1H NMR(500MHz,Chloroform-d)δ:9.26(s,1H),8.05 -8.00(m,1H),7.94(d,J＝8.2Hz,1H),7.92(s,1H),7.81(d,J＝8.2Hz,1H),7.73 (dd,J＝5.0,1.3Hz,1H),7.70-7.61(m,1H),7.54(t,J＝7.0Hz,1H),7.42(dd,J＝ 5.0,3.0Hz,1H).13CNMR(125MHz,Chloroform-d)δ:152.48,147.54,142.29, 136.61,130.55,127.64,126.80,126.71,126.33,126.04,123.16,115.78.MS-ESI m/z: calcd for C13H9NS[M+H]+:212.0456；found:212.0529.
化合物YKL-42
白色固体，产率：79％；1H NMR(500MHz,Chloroform-d)δ:9.45(s,1H),9.33 (s,1H),8.75(s,1H),8.29-8.19(m,1H),8.07(t,J＝9.4Hz,1H),7.99(s,1H),7.93 (d,J＝8.2Hz,1H),7.77(t,J＝7.6Hz,1H),7.75-7.65(m,2H),7.65(t,J＝7.5Hz, 1H).13C NMR(125MHz,Chloroform-d)δ:152.97,152.45,150.08,143.73,136.44, 134.15,131.85,130.86,128.63,127.92,127.75,127.71,127.64,127.26,126.85, 125.04,121.35.MS-ESIm/z:calcd for C18H12N2[M+H]+:257.1000；found:257.1076.
化合物YKL-43
白色固体，产率：80％；1H NMR(500MHz,Chloroform-d)δ:9.46(s,2H),9.37 (s,1H),9.27(s,1H),8.12(s,1H),8.04(dd,J＝8.3,1.1Hz,1H),7.93(d,J＝8.2Hz, 1H),7.77(t,J＝7.5Hz,1H),7.68(t,J＝7.5Hz,1H).13C NMR(125MHz, Chloroform-d)δ:158.22,155.09,153.25,145.63,136.24,132.71,131.17,128.30, 128.20,127.74,127.02,117.23.MS-ESI m/z:calcd for C13H9N3[M+H]+:208.0796； found:208.0868.
化合物YKL-44
白色固体，产率：83％；1H NMR(500MHz,Chloroform-d)δ:9.36(s,1H),8.75 (d,J＝5.4Hz,2H),8.17(s,1H),8.07-7.99(m,3H),7.92(d,J＝8.2Hz,1H),7.80- 7.71(m,1H),7.70-7.63(m,1H).13C NMR(125MHz,Chloroform-d)δ:152.87, 150.45,148.29,146.68,136.28,130.95,128.56,128.10,127.66,127.20,121.09, 117.68.MS-ESI m/z:calcd forC14H10N2[M+H]+:207.0844；found:207.0918.
化合物YKL-45
白色固体，产率：85％；1H NMR(500MHz,Chloroform-d)δ:9.35(s,1H),8.44 (s,1H),8.24(s,1H),8.10(s,1H),8.01(dd,J＝8.5,1.8Hz,1H),7.98(d,J＝8.2Hz, 1H),7.87(d,J＝8.2Hz,1H),7.68(t,J＝6.9Hz,1H),7.59-7.45(m,2H),6.67(s, 1H),5.30(s,1H).13CNMR(125MHz,Chloroform-d)δ:152.72,152.22,136.93, 136.20,131.84,130.33,128.47,127.57,127.39,126.77,126.47,124.86,121.62, 119.68,115.83,111.28,103.52.MS-ESIm/z:calcd for C17H12N2[M+H]+:245.1000； found:245.1073.
化合物YKL-46
白色固体，产率：61％；1H NMR(500MHz,Chloroform-d)δ:9.22(s,1H),8.01 (s,1H),7.94(d,J＝8.3Hz,1H),7.83(d,J＝8.3Hz,1H),7.67(t,J＝6.9Hz,1H), 7.58-7.49(m,2H),7.12(d,J＝3.4Hz,1H),6.57(dd,J＝3.4,1.8Hz,1H).13C NMR (125MHz,Chloroform-d)δ:154.15,152.60,143.44,143.01,136.40,130.74,127.74, 127.72,126.92,126.88,114.11,112.12,108.25.MS-ESI m/z:calcd for C13H9NO [M+H]+:196.0684；found:196.0756.
化合物YKL-47
白色固体，：产率：58％；1H NMR(500MHz,Chloroform-d)δ:9.22(s,1H),8.15 (s,0H),7.94(d,J＝8.2Hz,1H),7.79(d,J＝8.2Hz,1H),7.75(s,1H),7.66(t,J＝6.9 Hz,1H),7.57-7.49(m,2H),6.95(d,J＝1.8Hz,1H).13C NMR(125MHz, Chloroform-d)δ:152.59,145.65,143.89,141.33,136.52,130.63,127.71,127.66, 127.17,126.71,126.47,115.39,108.52.MS-ESI m/z:calcd for C13H9NO[M+H]+: 196.0684；found:196.0756.
实施例5：3-芳基异喹啉衍生物YKL-1～YKL-47对植物病原真菌的抑菌活性测定及结果
1)供试药剂：3-芳基异喹啉衍生物YKL-1～YKL-47。
2)供试菌种：核盘菌、立枯丝核菌、禾谷镰刀菌、番茄灰霉病菌、辣椒疫霉菌以及稻瘟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H-01～H-22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100μg/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：
表1化合物YKL-1～YKL-47在50μg/mL浓度下的抗植物病真原菌活性
从表1的实验数据可知，合成得到的3-芳基异喹啉小檗碱衍生物YKL-1～ YKL-47对6种植物病原真菌表现出不同程度的抑制作用。其中，化合物YKL-44、 YKL-42、YKL-46和YKL-47表现出较为广谱的抗菌活性，在50μg/mL浓度下对多种植物病原真菌的抑制率均在50％以上。因此我们在不同浓度梯度下对这些化合物进行了抗菌活性测定，并在表2中计算了相关的EC50值。
表2高活性3-芳基异喹啉小檗碱衍生物对植物病原真菌的EC50值(μg/mL)
注：“-”表示未测定或未计算
从表2的实验数据可知，化合物YKL-46对于立枯丝核菌表现出最强的抗菌活性，其EC50值为5.550μg/mL。此外，YKL-46对于其它5种测试真菌也表现出较好的抗菌作用，EC50值在9.281～30.920μg/mL之间。综合表1和表2的活性数据，我们发现大多数3-芳基异喹啉衍生物对于立枯丝核菌的抗菌活性优于对其它5种植物病原真菌的抗菌活性。
Claims (8)
1.本发明涉及3-芳基异喹啉衍生物在防治农业病原菌中的用途。
2.根据权利要求1所述的用途，其中，3-芳基异喹啉衍生物共具47种不同的化学结构，具有如下的分子结构特征：
3.根据权利要求1至2所述的用途，其中，3-芳基异喹啉衍生物在防治核盘菌病中的用途。
4.根据权利要求1至2所述的用途，其中，3-芳基异喹啉衍生物在防治立枯丝核病中的用途。
5.根据权利要求1至2所述的用途，其中，3-芳基异喹啉衍生物在防治禾谷镰刀菌病中的用途。
6.根据权利要求1至2所述的用途，其中，3-芳基异喹啉衍生物在防治番茄灰霉病中的用途。
7.根据权利要求1至2所述的用途，其中，3-芳基异喹啉衍生物在防治辣椒疫霉病中的用途。
8.根据权利要求1至2所述的用途，其中，肉桂酸衍生物在防治稻瘟病中的用途。
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