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• 三唑类化合物是一类重要的五元杂环化合物, 作为农药的一大组成部分, 在杀虫、杀菌、除草、植物生长等领域受到广泛关注^[1~5], 商品化药物如三唑磷、粉唑醇、多效唑. 1, 2, 3-三唑类化合物因其易形成配位键、氢键而和生物分子靶标结合的特点, 在药物开发领域得到广泛应用, 如Mao等^[6]设计合成了一系列含1, 2, 3-三唑基团的N-吡啶基吡唑衍生物, 其中部分化合物在25 mg/L浓度下对东方粘虫的杀虫活性达到100%; Wang等^[2]报道了一类5-甲基-1H-1, 2, 3-三唑-4-酰胺(酯)衍生物, 生测结果表明其对尖音库蚊有很好的杀虫活性.利用点击化学反应可以简易高效地合成1, 2, 3-三唑类化合物, 也促使其成为国内外药物设计的研究热点^[7].

  阿维菌素是由链霉菌Streptomyces avermitilis产生的一类以阿维菌素B1a (Avermectin B1a, 图 1)为主要成分的大环内酯类抗生素, 具有优良的杀虫杀螨和抗寄生虫活性^{[8, 9]}.阿维菌素通过作用于谷氨酸门控氯离子通道和GABA受体, 造成氯离子内流, 信号传导受阻, 使虫体麻痹死亡, 对哺乳动物具有较高的安全性^[10].由于其广谱、高效、低毒等特点, 使得阿维菌素成为中国市场上的主要杀虫剂品种之一, 同时也造成害虫对阿维菌素的抗性逐年增加, 因此对阿维菌素母体进行结构改造以改良其生物活性一直受到科研工作者的关注^[11~14].大量实验研究表明, 在阿维菌素B1a 4″位引入胺或者酰胺结构更利于改良其生物活性, 最具代表性的甲氨基阿维菌素(Emamectin, 图 1)对鳞翅目害虫(如小菜蛾)的活性比阿维菌素提高了1500倍^[15], 乙酰氨基阿维菌素(Eprinomectin, 图 1)以其对哺乳动物的高安全性广泛应用于治疗奶牛体内外寄生虫^[16], Zhang等^[11]报道的部分4″-磺酰胺类阿维菌素衍生物对朱砂叶螨和豆芽的杀虫活性为阿维菌素的10倍.本工作通过酰胺化和点击反应方法将酰胺基团和1, 2, 3-三唑环引入阿维菌素B1a 4″位, 设计合成了一系列未见文献报道的含酰胺结构的4″-阿维菌素三唑类衍生物, 采用¹H NMR、¹³C NMR和HRMS确认了其结构, 并测试了目标化合物对朱砂叶螨、桃蚜和秀丽隐杆线虫的杀虫活性.

  图 1

  

  图 1.  阿维菌素B1a、甲氨基阿维菌素和乙酰氨基阿维菌素的分子结构

  Figure 1.  Structures of avermectin B1a, emamectin and eprinomectin

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  1.   结果与讨论

  1.1   合成讨论及波谱分析

  在合成化合物7的过程中, 使用烯丙氧羰基选择性保护5位羟基, 需要控制温度在-20~-25 ℃之间, 否则4″位羟基也会参与反应, 产生难以分离的副产物.采用斯文氧化的方法合成化合物8, 活性较弱的二氯磷酸苯酯取代草酰氯作为去质子试剂, 反应温度控制在-15 ℃左右, 反应产生的二甲硫醚气味很大, 而且高毒, 需严格在通风橱中操作.由化合物8合成化合物9是非常关键的一步, 文献报道反应在50 ℃条件下进行, 却发现副产物较多, 而且不易分离, 故对反应温度进行调节.当反应温度为30 ℃时, 副产物明显减少, 但原料难以反应完全, 需大大延长反应时间; 当反应温度为40 ℃时, 副产物较少, 反应3 h即可反应完全, 因此选择40 ℃作为最佳反应温度.

  在合成目标化合物11a~11l时, 硫酸铜和抗坏血酸钠应先用水溶解后, 再加入到化合物10的甲醇溶液中, 否则易结块, 影响反应速率.由于反应底物在强酸强碱条件下不稳定, 使用四三苯基膦钯和硼氢化钠脱除烯丙氧羰基时, 应加入醋酸铵, 使反应体系酸碱度在适宜范围.

  以目标化合物11l为例, 进行核磁氢谱和碳谱分析. δ 9.07, 8.13处的三重峰(J＝5.8 Hz)和双峰(J＝9.6 Hz)归属于CONH上的活泼氢. δ 7.95处的单峰为三唑环C＝CH上的氢.苯环上的氢的δ值在7.46~7.94左右.与酰胺基团相连的CH₂的化学位移分别出现在δ 5.04~5.43和4.38~4.75, 和阿维菌素B1a母体氢的化学位移相重合. δ 3.38, 3.34处的两个单峰为两个糖环上的甲氧基氢的吸收峰. δ 1.18, 1.10, 0.99处的三个双峰分别为阿维菌素B1a母体6', 6″, 12a位置的甲基氢的吸收峰. δ在170.7, 166.2处的峰为羰基碳原子的信号峰.

  图式 1

  

  图式 1.  目标化合物合成路线

  Scheme 1.  Synthetic route of target compounds

  11a: R＝2,4-Cl₂C₆H₃; 11b: R＝2-(4-chlorophenyl)-3-methylbutyl; 11c: R＝2-CF₃C₆H₄; 11d: R＝2-PhC₆H₄; 11e: R＝4-ClC₆H₄; 11f: R＝4-CH₃OC₆H₄CH₂; 11g: R＝4-CH₃C₆H₄CH₂; 11h: R＝4-NO₂C₆H₄CH₂; 11i: R＝3-Me-2-H₂NC₆H₃CH₂; 11j: R＝2-NO₂C₆H₄; 11k: R＝4-F-C₆H₄; 11l: R＝Ph

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  1.2   杀虫活性

  目标化合物11a~11l对朱砂叶螨(T. cinnabarinus)、桃蚜(M. persicae)和秀丽隐杆线虫(C. elegans)的杀虫活性数据列于表 1.在0.1 μg/mL浓度下, 化合物11a~11l对朱砂叶螨表现出良好的杀虫活性, 大多数化合物对朱砂叶螨的致死率达到70%以上, 其中化合物11b和11e对朱砂叶螨的致死率超过80%, 但较对照药阿维菌素低(92.4%); 在50 μg/mL浓度下, 化合物11b, 11e, 11f, 11g, 11h和11i对桃蚜的致死率为72.3%~86.4%, 化合物11i (86.4%)对桃蚜的杀虫活性与阿维菌素(85.3%) B1a相当; 在1 μg/mL浓度下, 化合物11d, 11e, 11f, 11k和11l对秀丽隐杆线虫的杀虫活性较差, 死亡率小于50%, 低于对照药剂阿维菌素B1a (61.8%); 化合物11b (83.7%), 11c (72.4%), 11i (74.6%)表现出优于阿维菌素B1a的杀虫活性.

  表 1

  

  表 1  目标化合物11a~11l的杀虫活性(死亡率/%)

  Table 1.  Insecticidal activities (mortality/%) of target compounds 11a~11l

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  Compd.	T. cinnabarinus (0.1 μg/mL)	M. persicae (50 μg/mL)	C. elegans (1 μg/mL)
  11a	71.7	56.3	63.1
  11b	83.5	73.4	83.7
  11c	77.6	47.2	72.4
  11d	46.3	49.9	28.2
  11e	81.2	72.3	46.8
  11f	75.7	78.8	43.4
  11g	70.2	75.7	52.7
  11h	64.6	72.9	57.8
  11i	71.4	86.4	74.6
  11j	71.8	33.5	52.3
  11k	66.2	58.1	35.5
  11l	67.1	65.6	48.6
  Avermectin B1a	92.4	85.3	61.8

  表 1数据也表明, 目标化合物取代基的变化与其杀虫活性之间存在一定的关系: (1)对朱砂叶螨, 取代基为苯基或苄基, 对杀虫活性无明显影响.当苯环对位引入氯原子时, 活性有所提高, 如化合物11b活性提高到83.5%.在苯环邻位引入空间位阻较大的苯基(化合物11d)时, 杀虫活性明显降低. (2)对桃蚜, 当取代基为苄基时, 杀虫活性普遍较好, 均达到70%以上.当引入吸电子基团时, 杀虫活性降低, 如化合物11c对桃蚜的杀虫活性仅为47.2%.当取代基为苄基时, 亲水基团如NH₂(11i)的引入, 杀虫活性提高至86%. (3)对秀丽隐杆线虫, 目标化合物的杀虫活性普遍较差, 说明所引入的苯基/苄基取代基团不利于提高阿维菌素对秀丽隐杆线虫的杀虫活性, 但仍有部分目标化合物表现出较好的杀虫活性, 如化合物11b对秀丽隐杆线虫的杀虫活性达到83.7%.

  2.   结论

  以阿维菌素B1a为结构骨架, 采用活性亚结构拼接的原理, 合成了一系列含酰胺结构的4″-阿维菌素三唑类衍生物, 借助于¹H NMR, ¹³C NMR和HRMS手段对目标化合物进行结构确证.初步的生测结果表明, 部分目标化合物对朱砂叶螨、桃蚜和秀丽隐杆线虫表现出较好的杀虫活性, 其中化合物11b在50 μg/mL浓度下对桃蚜的杀虫活性为86.4%, 化合物11i在1 μg/mL浓度下对秀丽隐杆线虫具有83.7%的杀虫活性, 均优于阿维菌素, 进一步的结构优化和构效关系研究目前正在进行中.

  3.   实验部分

  3.1   仪器与试剂

  质谱采用Bruker Daltonics Bio-TOF-Q Ⅲ型质谱仪(ESIMS)测定; 天津光学仪器厂Ry-1G熔点仪, 温度计未经校正.核磁共振波谱使用Bruker Avance 300型.核磁共振仪测定(四甲基硅烷TMS为内标).阿维菌素B1a由内蒙古嘉宝仕生物科技股份有限公司提供, 纯度为90%.所有试剂为国产市售分析纯.

  3.2   实验方法

  3.2.1   中间体2, 5a~5l, 7~9的合成

  中间体2参照文献[17]方法制备, 中间体5a~5l参照文献[18~24]方法制备, 中间体7~9参照文献[25]方法制备.

  3.2.2   4″-(叠氮乙酰胺基)阿维菌素B1a (10)的合成

  向100 mL圆底烧瓶中加入4.80 g (5.02 mmol)化合物9, 用30 mL二氯甲烷溶解, 加入1.02 g (10.08 mmol)三乙胺, 在冰浴和氮气保护下, 滴加5 mL叠氮乙酰氯(0.72 g, 6.05 mmol)的二氯甲烷溶液, 滴加完毕后缓慢升温至室温, 薄层色谱(TLC)检测至反应完全, 反应液依次用稀盐酸溶液和饱和食盐水洗涤, 有机相用无水Na₂SO₄干燥, 过滤, 浓缩至干, 残留物经柱层析[V(石油醚)：V(乙酸乙酯)＝1：1]分离得淡黄色泡沫状固体3.62 g, 收率69%, m.p. 150~152 ℃. ¹H NMR (300 MHz, CDCl₃) δ: 6.44 (d, J＝10.0 Hz, 1H, CONH), 5.67~6.06 (m, 5H, H-9, CH₂＝CHCH₂O, H-23, H-10, H-11), 5.58~5.69 (m, 2H, H-22, H-3), 5.26~5.56 (m, 5H, H-1″, CH₂＝CHCH₂O, H-19, H-5), 4.92~5.06 (m, 1H, H-15), 4.57~4.83 (m, 5H, CH₂＝CHCH₂O, H-1', H8a×2), 4.36~4.53 (m, 1H, H-5″), 3.54~4.19 (m, 10H, 7-OH, CH₂N₃, H-6, H-13, H-17, H-5', H-5″, H-3', H-3″), 3.35~3.51 (m, 8H, H-2, H-4', 3″-OCH_3, 3'-OCH₃), 3.23 (t, J＝9.0 Hz, 1H, H-4″), 2.46~2.60 (m, 1H, H-12), 2.20~2.37 (m, 4H, H-16×2, H-24, H-2″), 1.98~2.12 (m, 2H, H-2', H-20), 1.83 (s, 3H, Me4a), 1.41~1.79 (m, 10H, H-20, H-26, H-27×2, H-2', H-2″, H-18, Me-14a), 1.08~1.37 (m, 9H, Me-6', Me-6″, Me-12a), 0.79~1.02 (m, 10H, Me-28, Me-24a, Me-26a, H-18); ¹³C NMR (75 MHz, DMSO-d₆) δ: 170.2, 168.2, 154.3, 140.1, 136.9, 135.1, 134.9, 132.2, 130.0, 128.4, 125.2, 123.1, 120.9, 118.3, 98.1, 95.5, 94.8, 81.6, 80.7, 80.1, 79.0, 77.9, 74.1, 72.9, 68.1, 67.1, 66.8, 65.3, 59.8, 55.9, 55.1, 50.7, 48.3, 45.4, 35.9, 34.7, 34.2, 33.9, 31.1, 30.3, 27.1, 26.5, 20.8, 20.1, 19.0, 18.2, 17.0, 16.2, 14.6, 14.2, 13.2, 11.8; HRMS (ESI) calcd for C₅₄H₇₉N₄O₁₆ (M+H)⁺: 1039.5491, found 1039.5509.

  3.2.3   目标化合物11a~11l的合成

  向100 mL圆底烧瓶中加入3.10 g中间体10 (2.99 mmol), 中间体5 (9.00 mmol), 溶于27 mL甲醇中, 后加入3 mL含有五水硫酸铜(20 mg)和抗坏血酸钠(40 mg)的水溶液, 室温反应过夜, TLC检测, 原料全部反应完全后, 加入水30 mL, 二氯甲烷萃取(300 mL×3), 合并有机相, 无水硫酸钠干燥, 减压旋转蒸发除去溶剂后溶于30 mL甲醇/四氢呋喃(V：V＝1：1)的混合溶剂中, 加入4.60 g乙酸铵(59.7 mmol), 冰盐浴10 min后, 依次加入0.03 g硼氢化钠(0.79 mmol), 0.14 g四三苯基膦钯(0.12 mmol), 0.03 g硼氢化钠(0.79 mmol), 约10 min后TLC检测原料反应完全, 减压蒸发除去溶剂, 加入20 mL水, 二氯甲烷120 mL分3次萃取, 无水硫酸钠干燥有机相, 减压浓缩后, 以石油醚/乙酸乙酯(V：V＝1：4)进行柱层析洗脱, 得到目标化合物11a~11l.

  4″-(1-(4-(2, 4-二氯苯甲酰胺基)-1H-1, 2, 3-三唑基)乙酰胺基)阿维菌素B1a (11a):黄色固体, 产率64%. m.p. 188~190 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 9.06 (t, J＝5.8 Hz, 1H, NHCO), 8.14 (d, J＝9.8 Hz, 1H, NHCO), 7.94 (s, 1H, C＝CHN), 7.67 (s, 1H, ArH), 7.48 (s, 1H, ArH), 7.47 (s, 1H, ArH), 5.48~5.95 (m, 5H, H23, H10, H-11, H-22, H-9), 5.33 (s, 2H, NCH₂), 5.09~5.27 (m, 3H, H-1″, H-19, H-3), 4.76~4.90 (m, 1H, H-15), 4.38~4.75 (m, 6H, H-1', H-8a×2, H-5″, NHCH₂), 4.23~4.35 (m, 1H, H-5), 3.46~4.11 (m, 8H, 7-OH, 23-OH, H-6, H-13, H-17, H-5', H-3', H-3″), 3.01~3.44 (m, 9H, H-2, H-4', H-4″, 3″-OCH₃, 3'-OCH₃), 2.53~2.68 (m, 1H, H-12), 2.02~2.33 (m, 4H, H-16×2, H-24, H-2″), 1.20~1.98 (m, 15H, H-20×2, Me-4a, H-26, H-27×2, H-2'×2, H-2″, H-18, Me-14a), 1.19 (d, J＝6.0 Hz, 3H, Me-6'), 1.09 (d, J＝6.7 Hz, 3H, Me-6″), 1.00 (d, J＝6.3 Hz, 3H, Me-12a), 0.79~1.02 (m, 10H, Me-28, Me-24a, Me-26a, H-18); ¹³C NMR (75 MHz, DMSO-d₆) δ: 170.1, 166.2, 165.5, 154.2, 144.3, 140.0, 136.8, 135.5, 135.1, 134.6, 132.1, 131.4, 130.4, 130.0, 129.1, 128.3, 127.2, 125.1, 124.3, 123.1, 120.8, 118.2, 98.1, 95.5, 94.7, 81.6, 80.6, 80.0, 79.2, 79.0, 77.8, 74.0, 72.8, 68.2, 68.0, 67.1, 66.8, 65.4, 55.9, 55.1, 51.7, 48.5, 45.4, 40.6, 35.8, 34.9, 34.7, 34.2, 33.8, 31.0, 30.2, 27.0, 20.1, 18.9, 18.2, 17.0, 16.2, 14.6, 13.1, 11.7; HRMS (ESI) calcd for C₆₀H₈₂Cl₂N₅O₁₅ [M+H]⁺ 1182.5184, found 1182.5199.

  4″-(1-(4-(2-(4-氯苯基)-3-甲基丁酰胺基)-1H-1, 2, 3-三唑基)乙酰胺基)阿维菌素B1a (11b):黄色固体, 产率56%. m.p. 210~212 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.58 (t, J＝5.4 Hz, 1H, NHCO), 8.12 (d, J＝9.7 Hz, 1H, NHCO), 7.76 (s, 1H, C＝CHN), 7.25~7.45 (m, 4H, ArH), 5.57~5.94 (m, 5H, H-23, H-10, H-11, H-22, H-9), 5.33 (s, 2H, NCH₂), 5.06~5.25 (m, 3H, H-1″, H-19, H-3), 4.75~4.92 (m, 1H, H-15), 3.93~4.72 (m, 7H, H-1', H-8a×2, H-5″, NHCH₂, H-5), 3.50~3.91 (m, 7H, 7-OH, H-6, H-13, H-17, H-5', H-3', H-3″), 2.99~3.46 (m, 10H, COCH, H-2, H-4', H-4″, 3″-OCH₃, 3'-OCH₃), 2.51~2.70 (m, 1H, H-12), 2.01~2.35 (m, 6H, H-16×2, H-24, H-2″, H-2', H-20), 1.22~1.98 (13H, H-2', H-20, Me-4a, H-26, H-27×2, H-2″, H-18, Me-14a), 0.97~1.23 (m, 9H, Me-6', Me-6″, Me-12a), 0.79~1.02 (m, 13H, Me-28, Me-24a, Me-26a, H-18, CHCH₃), 0.60 (d, J＝6.7 Hz, 3H, CHCH₃); ¹³C NMR (75 MHz, DMSO-d₆) δ: 170.7, 166.2, 165.1, 144.7, 141.3, 136.2, 136.2, 135.6, 135.1, 134.8, 133.0, 129.3, 128.3, 125.2, 124.4, 119.9, 118.5, 118.2, 98.1, 95.4, 94.7, 81.6, 81.1, 80.2, 80.0, 79.2, 79.0, 74.0, 72.8, 68.2, 67.8, 66.9, 66.8, 65.3, 55.9, 55.0, 51.6, 48.5, 45.7, 40.7, 35.9, 35.0, 34.6, 34.1, 33.9, 31.0, 30.2, 27.0, 20.1, 19.5, 18.2, 17.0, 16.2, 14.6, 13.1, 11.7; HRMS (ESI) calcd for C₆₄H₉₁ClN₅O₁₅ [M+H]⁺ 1204.6200, found 1204.6223.

  4″-(1-(2-三氟甲基苯甲酰胺基)-1H-1, 2, 3-三唑基)乙酰胺基)阿维菌素B1a (11c):黄色固体, 产率42%. m.p. 205~207 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 9.05 (t, J＝5.7 Hz, 1H, NHCO), 8.15 (d, J＝9.6 Hz, 1H, NHCO), 7.91 (s, 1H, C＝CHN), 7.46~7.81 (m, 4H, ArH), 5.51~5.97 (m, 5H, H-23, H-10, H-11, H-22, H-9), 5.32 (s, 2H, NCH₂), 5.08~5.26 (m, 3H, H-1″, H-19, H-3), 4.75~4.92 (m, 1H, H-15), 4.40~4.75 (m, 6H, H-1', H-8a×2, H-5″, NHCH₂), 4.21~4.33 (m, 1H, H-5), 3.51~4.13 (m, 7H, 7-OH, H-6, H-13, H-17, H-5', H-3', H-3″), 2.99~3.46 (m, 9H, H-2, H-4', H-4″, 3″-OCH₃, 3'-OCH₃), 2.53~2.72 (m, 1H, H-12), 1.95~2.35 (m, 5H, H-16×2, H-24, H-2″, H-20), 1.25~1.98 (m, 14H, H-20, Me-4a, H-26, H-27×2, H-2'×2, H-2″, H-18, Me-14a), 0.97~1.25 (m, 9H, Me-6', Me-6″, Me-12a), 0.59~0.97 (m, 10H, Me-28, Me-24a, Me-26a, H-18); ¹³C NMR (75 MHz, DMSO-d₆) δ: 170.8, 167.2, 166.3, 144.6, 141.4, 136.3, 136.3, 135.8, 135.2, 132.3, 129.8, 129.3, 128.7, 126.5, 126.2, 126.2, 126.1, 126.0, 125.6, 124.2, 122.0, 120.0, 118.4, 98.2, 95.5, 94.8, 81.8, 81.2, 80.3, 80.1, 79.3, 79.1, 74.1, 73.0, 68.3, 68.1, 67.9, 66.9, 65.4, 56.0, 55.1, 51.8, 48.6, 45.7, 40.9, 36.3, 35.0, 31.4, 30.2, 27.1, 20.1, 19.5, 18.2, 17.0, 16.3, 14.7, 13.2, 11.8; HRMS (ESI) calcd for C₆₁H₈₃F₃N₅O₁₅ [M+H]⁺ 1182.5838, found 1182.5861.

  4″-(1-(2-苯基苯甲酰胺基)-1H-1, 2, 3-三唑基)乙酰胺基)阿维菌素B1a (11d):黄色固体, 产率45%. m.p. 187~ 189 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.75 (t, J＝5.8 Hz, 1H, NHCO), 8.16 (d, J＝9.8 Hz, 1H, NHCO), 7.29~7.69 (m, 10H, ArH, C＝CHN), 5.51~5.98 (m, 5H, H-23, H-10, H-11, H-22, H-9), 5.34 (s, 2H, NCH₂), 5.03~5.26 (m, 3H, H-1″, H-19, H-3), 4.76~4.96 (m, 1H, H-15), 4.25~4.75 (m, 7H, H-1', H-8a×2, H-5″, NHCH₂, H-5), 3.50~4.16 (m, 8H, 7-OH, 23-OH, H-6, H-13, H-17, H-5', H-3', H-3″), 3.00~3.49 (m, 9H, H-2, H-4', H-4″, 3″-OCH_3, 3'-OCH₃), 2.53~2.71 (m, 1H, H-12), 2.02~2.36 (m, 4H, H-16×2, H-24, H-2″), 1.27~1.96 (m, 15H, H-20×2, Me-4a, H-26, H-27×2, H-2'×2, H-2″, H-18, Me-14a), 0.98~1.26 (m, 9H, Me-6', Me-6″, Me-12a), 0.63~0.97 (m, 10H, Me-28, Me-24a, Me-26a, H-18); ¹³C NMR (75 MHz, DMSO-d₆) δ: 170.8, 169.2, 166.2, 144.5, 141.3, 140.2, 139.3, 136.9, 136.2, 135.7, 135.2, 134.9, 132.0, 131.9, 131.5, 129.9, 129.4, 128.8, 128.7, 128.5, 128.2, 127.8, 127.1, 127.0, 125.3, 124.0, 120.0, 118.5, 118.2, 98.2, 95.5, 94.8, 81.7, 81.1, 80.2, 80.0, 79.3, 79.0, 74.0, 72.9, 68.2, 67.9, 67.0, 66.8, 65.4, 55.9, 55.1, 51.6, 48.6, 45.7, 40.7, 35.9, 34.7, 34.2, 33.9, 31.1, 30.2, 27.1, 20.1, 19.5, 18.2, 17.0, 16.2, 14.7, 13.2, 11.8; HRMS (ESI) calcd for C₆₆H₈₈N₅O₁₅ [M+H]⁺ 1190.6277, found 1190.6295.

  4″-(1-(4-氯苯甲酰胺基)-1H-1, 2, 3-三唑基)乙酰胺基)阿维菌素B1a (11e):白色固体, 产率41%. m.p. 176~178 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 9.15 (t, J＝5.8 Hz, 1H, NHCO), 8.12 (d, J＝9.7 Hz, 1H, NHCO), 7.76~7.96 (m, 3H, ArH, C＝CHN), 7.54 (d, J＝8.6 Hz, 2H, ArH), 5.51~6.01 (m, 5H, H-23, H-10, H-11, H-22, H-9), 5.02~5.35 (m, 5H, H-1″, H-19, H-3, NCH₂), 4.76~4.89 (m, 1H, H-15), 4.37~4.75 (m, 6H, H-1', H-8a×2, H-5″, NHCH₂), 4.22~4.33 (m, 1H, H-5), 3.50~4.14 (m, 8H, 7-OH, 23-OH, H-6, H-13, H-17, H-5', H-3', H-3″), 3.02~3.49 (m, 9H, H-2, H-4', H-4″, 3″-OCH₃, 3'-OCH₃), 2.54~2.70 (m, 1H, H-12), 2.02~2.34 (m, 4H, H-16×2, H-24, H-2″), 1.26~1.90 (m, 15H, H-20×2, Me-4a, H-26, H-27×2, H-2'×2, H-2″, H-18, Me-14a), 0.98~1.25 (m, 9H, Me-6', Me-6″, Me-12a), 0.59~0.98 (m, 10H, Me-28, Me-24a, Me-26a, H-18); ¹³C NMR (75 MHz, DMSO-d₆) δ: 170.7, 166.2, 165.1, 144.7, 141.3, 136.2, 136.2, 135.6, 135.1, 134.8, 133.0, 129.3, 128.3, 125.2, 124.4, 119.9, 118.5, 118.2, 98.1, 95.4, 94.7, 81.6, 81.1, 80.2, 80.0, 79.2, 79.0, 74.0, 72.8, 68.2, 67.8, 66.9, 66.8, 65.3, 55.9, 55.0, 51.6, 48.5, 45.7, 40.7, 35.9, 35.0, 34.6, 34.1, 33.9, 31.0, 30.2, 27.0, 20.1, 19.5, 18.2, 17.0 16.2, 14.6, 13.1, 11.7; HRMS (ESI) calcd for C₆₀H₈₃ClN₅O₁₅ [M+H]⁺ 1148.5574, found 1148.5602.

  4″-(1-(4-甲氧基苯乙酰胺基)-1H-1, 2, 3-三唑基)乙酰胺基)阿维菌素B1a (11f):白色固体, 产率37%. m.p. 142~144 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.50 (t, J＝5.6 Hz, 1H, NHCO), 8.14 (d, J＝9.9 Hz, 1H, NHCO), 7.83 (s, 1H, C＝CHN), 7.15(d, J＝8.6 Hz, 2H, ArH), 6.84 (d, J＝8.6 Hz, 2H, ArH), 5.51~6.00 (m, 5H, H-23, H-10, H-11, H-22, H-9), 5.33 (s, 2H, NCH₂), 5.03~5.26 (m, 3H, H-1″, H-19, H-3), 4.75~4.90 (m, 1H, H-15), 4.23~4.74 (m, 7H, H-1', H-8a×2, H-5″, NHCH₂, H-5), 3.50~4.15 (m, 11H, 7-OH, 23-OH, H-6, H-13, H-17, H-5', H-3', H-3″, PhOCH₃), 3.01~3.49 (m, 11H, H-2, H-4', H-4″, 3″-OCH_3, 3'-OCH₃, PhCH₂), 2.51~2.73 (m, 1H, H-12), 2.02~2.31 (m, 6H, H-16×2, H-24, H-2″, H-20, H-2'), 1.25~1.97 (m, 13H, H-20, Me-4a, H-26, H-27×2, H-2', H-2″, H-18, Me-14a), 0.99~1.25 (m, 9H, Me-6', Me-6″, Me-12a), 0.61~0.99 (m, 10H, Me-28, Me-24a, Me-26a, H-18); ¹³C NMR (75 MHz, DMSO-d₆) δ: 170.8, 170.4, 166.3, 158.0, 144.7, 141.4, 136.3, 135.7, 135.4, 135.2, 134.9, 133.3, 130.1, 129.0, 128.8, 128.4, 125.3, 124.3, 120.0, 118.6, 118.3, 113.7, 98.2, 95.5, 94.8, 81.7, 81.2, 80.3, 80.0, 79.3, 79.1, 74.1, 72.9, 68.3, 67.9, 67.0, 66.8, 65.4, 56.0, 55.1, 51.7, 48.5, 45.8, 41.9, 40.7, 35.9, 34.7, 34.6, 34.2, 33.9, 31.1, 30.3, 27.1, 20.8, 20.2, 19.6, 18.3, 17.1, 16.3, 14.7, 13.2, 11.8; HRMS (ESI) calcd for C₆₂H₈₈N₅O₁₆ [M+H]⁺ 1158.6226, found 1158.6238.

  4″-(1-(4-甲基苯乙酰胺基)-1H-1, 2, 3-三唑基)乙酰胺基)阿维菌素B1a (11g):黄色固体, 产率65%. m.p. 149~151 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.52 (t, J＝ 5.7 Hz, 1H, NHCO), 8.13 (d, J＝9.8 Hz, 1H, NHCO), 7.84 (s, 1H, C＝CHN), 7.06~7.23 (m, 4H, ArH), 5.49~5.98 (m, 5H, H-23, H-10, H-11, H-22, H-9), 5.33 (s, 2H, NCH₂), 5.02~5.26 (m, 3H, H-1″, H-19, H-3), 4.74~4.86 (m, 1H, H-15), 4.25~4.73 (m, 7H, H-1', H-8a×2, H-5″, NHCH₂, H-5), 3.49~4.13 (m, 8H, 7-OH, 23-OH, H-6, H-13, H-17, H-5', H-3', H-3″), 3.01~3.48 (m, 11H, H-2, H-4', H-4″, 3″-OCH₃, 3'-OCH₃, PhCH₂), 2.51~2.70 (m, 1H, H-12), 2.02~2.31 (m, 7H, H-16×2, H-24, H-2″, PhCH₃), 1.25~1.97 (m, 15H, H-20×2, Me-4a, H-26, H-27×2, H-2'×2, H-2″, H-18, Me-14a), 0.98~1.25 (m, 9H, Me-6', Me-6″, Me-12a), 0.56~0.98 (m, 10H, Me-28, Me-24a, Me-26a, H18); ¹³C NMR (75 MHz, DMSO-d₆) δ: 170.7, 170.4, 166.2, 157.9, 144.6, 141.3, 136.2, 135.6, 135.1, 134.8, 130.0, 128.9, 128.8, 128.3, 128.2, 125.2, 124.2, 119.9, 118.5, 118.2, 113.7, 98.1, 95.4, 94.7, 81.6, 81.1, 80.2, 79.9, 79.2, 79.0, 74.0, 72.8, 68.2, 67.8, 66.9, 66.8, 65.3, 55.9, 55.0, 51.6, 48.5, 45.7, 41.3, 40.7, 38.7, 35.8, 34.6, 34.4, 34.1, 33.8, 31.0, 30.2, 27.0, 20.1, 19.5, 18.2, 17.0, 16.2, 14.6, 13.1, 11.7; HRMS (ESI) calcd for C₆₂H₈₈N₅O₁₅ [M+H]⁺ 1142.6277, found 1142.6301.

  4″-(1-(4-硝基苯乙酰胺基)-1H-1, 2, 3-三唑基)乙酰胺基)阿维菌素B1a (11h):白色固体, 产率57%. m.p. 180~ 182 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 9.41 (t, J＝5.7 Hz, 1H, NHCO), 8.02~8.36 (m, 5H, NHCO, ArH), 7.95 (s, 1H, C＝CHN), 5.49~6.02 (m, 5H, H-23, H-10, H-11, H-22, H-9), 5.02~5.36 (m, 5H, H-1″, H-19, H-3, NCH₂), 4.77~4.95 (m, 1H, H-15), 4.37~4.75 (m, 6H, H-1', H-8a×2, H-5″, NHCH₂), 4.23~4.33 (m, 1H, H-5), 3.50~4.12 (m, 8H, 7-OH, 23-OH, H-6, H-13, H-17, H-5', H-3', H-3″), 3.02~3.49 (m, 11H, H-2, H-4', H-4″, 3″-OCH₃, 3'-OCH₃, PhCH₂), 2.52~2.73 (m, 1H, H-12), 2.02~2.33 (m, 6H, H-16×2, H-24, H-2″, H-20, H-2'), 1.26~1.90 (m, 13H, H-20, Me-4a, H-26, H-27×2, H-2', H-2″, H-18, Me-14a), 0.97~1.25 (m, 9H, Me-6', Me-6″, Me-12a), 0.61~0.97 (m, 10H, Me-28, Me-24a, Me-26a, H-18); ¹³C NMR (75 MHz, DMSO-d₆) δ: 170.8, 166.3, 164.6, 149.1, 141.3, 139.9, 136.3, 135.7, 135.2, 131.9, 131.5, 128.9, 128.7, 125.3, 124.6, 123.5, 120.0, 118.6, 118.3, 98.2, 95.5, 94.8, 81.7, 81.2, 80.3, 80.1, 79.3, 79.0, 74.1, 72.9, 68.3, 67.9, 67.0, 66.8, 65.4, 63.3, 56.0, 55.1, 51.7, 48.6, 45.7, 40.7, 36.0, 35.2, 34.7, 34.1, 31.3, 30.2, 27.1, 20.1, 19.5, 18.9, 18.8, 18.2, 17.0, 16.2, 14.6, 13.8, 13.6, 13.1, 11.8; HRMS (ESI) calcd for C₆₁H₈₅N₆O₁₇ [M+H]⁺ 1173.5971, found 1173.5993.

  4″-(1-(2-氨基-3-甲基苯乙酰胺基)-1H-1, 2, 3-三唑基)乙酰胺基)阿维菌素B1a (11i):黄色固体, 产率51%. m.p. 198~200 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.78 (t, J＝5.8 Hz, 1H, NHCO), 8.12 (d, J＝10.0 Hz, 1H, NHCO), 7.88 (s, 1H, C＝CHN), 7.41 (d, J＝7.1 Hz, 1H, ArH), 7.07 (d, J＝7.1 Hz, 1H, ArH), 6.46 (t, J＝7.6 Hz, 1H, ArH), 6.27 (s, 2H, NH₂Ar), 5.49~6.02 (m, 5H, H-23, H-10, H-11, H-22, H-9), 5.02~5.36 (m, 5H, H-1″, H-19, H-3, NCH₂), 4.75~4.96 (m, 1H, H-15), 4.35~4.75 (m, 6H, H-1', H-8a×2, H-5″, NHCH₂), 4.23~4.32 (m, 1H, H-5), 3.50~4.10 (m, 8H, 7-OH, 23-OH, H-6, H-13, H-17, H-5', H-3', H-3″), 3.01~3.49 (m, 11H, H-2, H-4', H-4″, 3″-OCH₃, 3'-OCH₃, PhCH₂), 2.52~2.73 (m, 1H, H-12), 2.02~2.33 (m, 8H, H-16×2, H-24, H-2″, H-20, PhCH₃), 1.25~1.97 (m, 14H, H-20, Me-4a, H-26, H-27×2, H-2'×2, H-2″, H-18, Me-14a), 0.97~1.25 (m, 9H, Me-6', Me-6″, Me-12a), 0.60~0.97 (m, 10H, Me-28, Me-24a, Me-26a, H-18); ¹³C NMR (75 MHz, DMSO-d₆) δ: 170.8, 169.3, 166.3, 147.8, 145.2, 141.3, 136.3, 135.6, 135.2, 134.9, 132.6, 128.4, 126.1, 125.3, 124.3, 123.1, 119.9, 118.5, 118.2, 114.5, 114.3, 98.1, 95.5, 94.7, 81.6, 81.1, 80.2, 80.0, 79.2, 79.0, 74.0, 72.8, 68.2, 67.9, 66.9, 66.8, 65.4, 55.9, 55.1, 51.6, 48.5, 45.7, 40.7, 35.9, 34.7, 34.2, 33.9, 31.0, 30.2, 27.0, 20.1, 19.5, 18.2, 17.6, 17.0, 16.2, 14.6, 13.2, 11.8; HRMS (ESI) calcd for C₆₂H₈₉N₆O₁₅ [M+H]⁺ 1157.6386, found 1157.6401.

  4″-(1-(2-硝基苯甲酰胺基)-1H-1, 2, 3-三唑基)乙酰胺基)阿维菌素B1a (11j):黄色固体, 产率72%. m.p. 188~ 190 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 9.23 (t, J＝5.7 Hz, 1H, NHCO), 8.15 (d, J＝9.9 Hz, 1H, NHCO), 8.00~ 8.08 (m, 1H, ArH), 7.94 (s, 1H, C＝CHN), 7.53~7.82 (m, 3H, ArH), 5.49~5.98 (m, 5H, H-23, H-10, H-11, H-22, H-9), 5.04~5.41 (m, 5H, H-1″, H-19, H-3, NCH₂), 4.74~4.97 (m, 1H, H-15), 4.33~4.74 (m, 6H, H1', H-8a×2, H-5″, NHCH₂), 4.18~4.31 (m, 1H, H-5), 3.49~4.13 (m, 8H, 7-OH, 23-OH, H-6, H-13, H-17, H-5', H-3', H-3″), 3.00~3.49 (m, 9H, H-2, H-4', H-4″, 3″-OCH₃, 3'-OCH₃), 2.51~2.73 (m, 1H, H-12), 2.02~2.35 (m, 6H, H-16×2, H-24, H-2″, H-20, H-2'), 1.25~1.97 (m, 13H, H-20, Me-4a, H-26, H-27×2, H-2', H-2″, H-18, Me-14a), 0.98~1.25 (m, 9H, Me-6', Me-6″, Me-12a), 0.57~0.97 (m, 10H, Me-28, Me-24a, Me-26a, H-18); ¹³C NMR (75 MHz, DMSO-d₆) δ: 170.8, 166.3, 165.5, 147.2, 144.2, 141.4, 136.3, 135.7, 135.2, 135.0, 133.6, 132.3, 130.9, 129.3, 128.4, 125.3, 124.4, 124.2, 120.0, 118.6, 118.3, 98.1, 95.5, 94.8, 81.6, 81.2, 80.2, 80.0, 79.3, 79.0, 74.1, 72.8, 68.3, 67.9, 67.0, 66.8, 65.4, 56.0, 55.1, 51.7, 48.5, 45.7, 40.7, 38.8, 35.9, 35.0, 34.7, 34.2, 33.9, 31.1, 30.3, 27.1, 20.2, 19.6, 18.3, 17.1, 16.3, 14.7, 13.2, 11.8; HRMS (ESI) calcd for C₆₀H₈₃N₆O₁₇ [M+H]⁺ 1159.5815, found 1159.5840.

  4″-(1-(4-氟苯甲酰胺基)-1H-1, 2, 3-三唑基)乙酰胺基)阿维菌素B1a (11k):白色固体, 产率43%. m.p. 200~202 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 9.10 (t, J＝5.7 Hz, 1H, NHCO), 8.12 (d, J＝10.0 Hz, 1H, NHCO), 7.92~ 7.99 (m, 3H, ArH, C＝CHN), 7.22~7.35 (m, 2H, ArH), 5.46~5.98 (m, 5H, H-23, H-10, H-11, H-22, H-9), 5.04~5.45 (m, 5H, H-1″, H-19, H-3, NCH₂), 4.76~4.96 (m, 1H, H-15), 4.33~4.75 (m, 6H, H-1', H-8a×2, H-5″, NHCH₂), 4.18~4.32 (m, 1H, H-5), 3.48~4.14 (m, 8H, 7-OH, 23-OH, H-6, H-13, H-17, H-5', H-3', H-3″), 2.97~3.48 (m, 9H, H-2, H-4', H-4″, 3″-OCH₃, 3'-OCH₃), 2.51~2.72 (m, 1H, H-12), 2.02~2.39 (m, 6H, H-16×2, H-24, H-2″, H-20, H-2'), 1.25~1.98 (m, 13H, H-20, Me-4a, H-26, H-27×2, H-2', H-2″, H-18, Me-14a), 0.98~1.25 (m, 9H, Me-6', Me-6″, Me-12a), 0.56~0.98 (m, 10H, Me-28, Me-24a, Me-26a, H-18); ¹³C NMR (75 MHz, DMSO-d₆) δ: 170.8, 166.3, 165.2, 162.4, 144.9, 141.3, 136.3, 135.7, 135.2, 134.9, 130.7, 130.7, 130.1, 130.0, 128.4, 125.3, 124.5, 120.0, 118.6, 115.4, 115.1, 98.1, 95.5, 94.8, 81.7, 81.2, 80.2, 80.0, 79.0, 74.0, 72.9, 68.2, 67.9, 67.0, 66.8, 65.4, 59.8, 55.9, 55.1, 51.6, 48.5, 45.7, 40.7, 35.9, 35.0, 34.7, 31.1, 30.2, 27.1, 26.5, 20.8, 20.1, 19.5, 18.2, 17.0, 16.2, 14.6, 14.1, 13.2, 11.8; HRMS (ESI) calcd for C₆₀H₈₃FN₅O₁₅ [M+H]⁺ 1132.5870, found 1132.5873.

  4″-(1-(苯甲酰胺基)-1H-1, 2, 3-三唑基)乙酰胺基)阿维菌素B1a (11l):黄色固体, 产率47%. m.p. 154~156 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 9.07 (t, J＝5.8 Hz, 1H, NHCO), 8.13 (d, J＝9.6 Hz, 1H, NHCO), 7.76~7.98 (m, 3H, ArH, C＝CHN), 7.40~7.57 (m, 3H, ArH), 5.49~5.98 (m, 5H, H-23, H-10, H-11, H-22, H-9), 5.04~5.43 (m, 5H, H-1″, H-19, H-3, NCH₂), 4.76~4.95 (m, 1H, H-15), 4.38~4.75 (m, 6H, H-1', H-8a×2, H-5″, NHCH₂), 4.19~4.34 (m, 1H, H-5), 3.51~4.13 (m, 8H, 7-OH, 23-OH, H-6, H-13, H-17, H-5', H-3', H-3″), 2.98~3.49 (m, 9H, H-2, H-4', H-4″, 3″-OCH₃, 3'-OCH₃), 2.51~2.73 (m, 1H, H-12), 2.02~2.36 (m, 5H, H-16×2, H-24, H-2', H-2″), 1.24~1.99 (m, 14H, H-20×2, Me-4a, H-26, H-27×2, H-2', H-2″, H-18, Me-14a), 0.97~1.24 (m, 9H, Me-6', Me-6″, Me-12a), 0.55~ 0.97 (m, 10H, Me-28, Me-24a, Me-26a, H-18); ¹³C NMR (75 MHz, DMSO-d₆) δ: 170.8, 166.2, 145.1, 141.3, 136.2, 135.7, 135.1, 134.5, 134.3, 131.2, 128.2, 127.4, 125.3, 124.4, 119.9, 118.5, 98.1, 95.5, 94.7, 81.7, 81.1, 80.2, 80.1, 79.2, 79.0, 74.0, 72.9, 70.4, 68.2, 67.9, 67.4, 67.0, 66.8, 65.4, 55.9, 55.1, 51.7, 48.5, 45.7, 35.0, 34.8, 34.2, 33.9, 31.1, 30.3, 27.1, 20.1, 19.5, 18.2, 17.0, 16.2, 14.6, 13.1, 11.8; HRMS (ESI) calcd for C₆₀H₈₄N₅O₁₅ [M+H]⁺ 1114.5964, found 1114.5981.

  3.3   生物活性测试

  3.3.1   目标化合物对朱砂叶螨和桃蚜的杀虫活性实验

  采用浸渍法测定目标化合物对桃蚜和朱砂叶螨的杀虫活性^[26].对于化合物, 用分析天平称取一定质量的目标化合物, 用含吐温-80的N, N-二甲基甲酰胺(DMF)溶解, 然后再用蒸馏水稀释到所需浓度, 每个处理三个重复, 设空白对照, 阿维菌素B1a作为对照药剂.

  选择带虫甘蓝叶, 留下3日龄桃蚜和4日龄朱砂叶螨, 将带虫叶片在药液中浸渍5 s, 晾干后记录虫数放入加有保湿滤纸的培养皿中, 加盖后放入24~27 ℃光照培养箱中培养.每个培养皿处理10头以上, 调查药后2 d后死活虫数, 并进行统计分析.

  3.3.2   目标化合物对秀丽隐杆线虫的杀虫活性实验

  采用触杀法测定目标化合物对秀丽隐杆线虫的杀线虫活性^[27].对于化合物, 用分析天平称取一定质量的目标化合物, 用甲醇溶解, 然后再用M9缓冲液稀释到2 μg/mL, 每个处理三个重复, M9缓冲液为空白对照, 阿维菌素B1a为对照药剂.

  取25 μL供试药液置于96孔培养板中, 加入25 μL浓度为2000条/mL的3日龄秀丽隐杆线虫, 培养板置于20 ℃恒温箱中, 24 h后检查死活虫数, 并进行统计分析.

  辅助材料(Supporting Information)  化合物10, 11a~ 11l的¹H NMR和¹³C NMR图谱.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.

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• 

  图 1  阿维菌素B1a、甲氨基阿维菌素和乙酰氨基阿维菌素的分子结构

  Figure 1  Structures of avermectin B1a, emamectin and eprinomectin

  下载: 全尺寸图片 幻灯片
  

  图式 1  目标化合物合成路线

  Scheme 1  Synthetic route of target compounds

  11a: R＝2,4-Cl₂C₆H₃; 11b: R＝2-(4-chlorophenyl)-3-methylbutyl; 11c: R＝2-CF₃C₆H₄; 11d: R＝2-PhC₆H₄; 11e: R＝4-ClC₆H₄; 11f: R＝4-CH₃OC₆H₄CH₂; 11g: R＝4-CH₃C₆H₄CH₂; 11h: R＝4-NO₂C₆H₄CH₂; 11i: R＝3-Me-2-H₂NC₆H₃CH₂; 11j: R＝2-NO₂C₆H₄; 11k: R＝4-F-C₆H₄; 11l: R＝Ph

  下载: 全尺寸图片 幻灯片

  表 1  目标化合物11a~11l的杀虫活性(死亡率/%)

  Table 1.  Insecticidal activities (mortality/%) of target compounds 11a~11l

  Compd.	T. cinnabarinus (0.1 μg/mL)	M. persicae (50 μg/mL)	C. elegans (1 μg/mL)
  11a	71.7	56.3	63.1
  11b	83.5	73.4	83.7
  11c	77.6	47.2	72.4
  11d	46.3	49.9	28.2
  11e	81.2	72.3	46.8
  11f	75.7	78.8	43.4
  11g	70.2	75.7	52.7
  11h	64.6	72.9	57.8
  11i	71.4	86.4	74.6
  11j	71.8	33.5	52.3
  11k	66.2	58.1	35.5
  11l	67.1	65.6	48.6
  Avermectin B1a	92.4	85.3	61.8

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