4"-脱氧阿维菌素脲类及硫脲类衍生物的合成与杀虫活性


农药学学报 2016, Vol. 18 Issue (5): 556-566	PDF

引用本文

张娜, 成丕乐, 南祥, 吴小兵, 刘映前, 余海涛, 张健, 杨程杰, 胡冠芳 . 4"-脱氧阿维菌素脲类及硫脲类衍生物的合成与杀虫活性[J]. 农药学学报, 2016, 18(5): 556-566,doi: 10.16801/j.issn.1008-7303.2016.0080 复制到剪切板

ZHANG Na, CHENG Pile, NAN Xiang, WU Xiaobing, LIU Yingqian, YU Haitao, ZHANG Jian, YANG Chengjie, HU Guanfang . Synthesis and insecticidal activity of 4"-deoxy-abamectin urea and thioure analogues[J]. Chinese Journal of Pesticide Science, 2016, 18(5): 556-566, doi:10.16801/j.issn.1008-7303.2016.0080 复制到剪切板

4"-脱氧阿维菌素脲类及硫脲类衍生物的合成与杀虫活性

张娜¹, 成丕乐¹, 南祥¹, 吴小兵¹, 刘映前¹, 余海涛², 张健¹, 杨程杰¹, 胡冠芳²

1. 兰州大学药学院药物化学研究所, 兰州 730000;
2. 甘肃省农业科学院植物保护研究所, 兰州 730000

收稿日期: 2016-05-06 录用日期: 2016-07-03.

基金项目: 国家自然科学基金项目（31371975；30800720）

作者简介: 张娜, 女, 硕士研究生, E-mail:zhangna14@lzu.edu.cn ;
^*刘映前, 通信作者 (Author for correspondence),男, 教授, 研究方向为药物分子设计与合成, E-mail:yqliu@lzu.edu.cn
胡冠芳, 共同通信作者 (Co-author for correspondence),男, 研究员, 研究方向为杂草防除, E-mail:huguanfang@126.com

摘要: 以构效关系为线索，根据类同合成法和活性官能团拼接策略，以阿维菌素为先导分子，在其4"-位引入硫脲或脲活性结构单元，合成了一系列酰基硫脲（9a~9o）和芳基脲（10a~10i）阿维菌素衍生物，所有目标化合物均经¹H NMR、MS和元素分析确证。室内杀虫活性测定结果表明：所有衍生物对朱砂叶螨Tetranychus cinnabarinus和甘蓝蚜Brevicoryne brassicae均表现出不同程度的毒杀活性，大部分化合物对甘蓝蚜的杀虫活性优于阿维菌素B1a，其中化合物9h对朱砂叶螨和甘蓝蚜的LC₅₀值分别为0.100和1.71 μmol/L，表现出很高的毒杀活性，化合物9o对甘蓝蚜的毒性最高，LC₅₀值为1.13 μmol/L。

关键词: 阿维菌素B1a 脲硫脲合成杀虫活性

Synthesis and insecticidal activity of 4"-deoxy-abamectin urea and thioure analogues

ZHANG Na¹, CHENG Pile¹, NAN Xiang¹, WU Xiaobing¹, LIU Yingqian¹, YU Haitao², ZHANG Jian¹, YANG Chengjie¹, HU Guanfang²

1. School of Pharmacy, Lanzhou University, Lanzhou 730000, China;
2. Institute of Plant Protection, Gansu Academy of Agricultural Sciences, Lanzhou 730000, China

Abstract: Based on SAR investigation, two series of abamectin analogues containing urea and acyl thiourea groups were designed according to analog synthesis and sub-structure. Their structures were confirmed by ¹H NMR, MS and elemental analysis. Their insecticidal activity was tested against Tetranychus cinnabarinus and Brevicoryne brassicae. All the tested compounds showed significant inhibitory activity against the above two insect species. Notably, the majority of those compounds exhibited high selectivity against B. brassicae, some of which were much better in comparison to abamectin. Especially, compound 9h displayed more potent activity than abamectin against the above two insect species, namely, T. cinnabarinus (LC₅₀=0.100 μmol/L) and B. brassicae (LC₅₀=1.71 μmol/L).Moreover, compound 9o showed superior activity against B. brassicae, with LC₅₀ value of 1.13 μmol/L.

Key words: abamectin urea acyl thiourea synthesis insecticidal activity

阿维菌素是由日本北里大学大村智等和美国Merck公司从链霉菌Streptomyces avermitilis分离获得的一组作用于昆虫神经元GABA受体的大环内酯类抗生素，对线虫、昆虫和螨虫均有驱杀作用，主要用于治疗畜禽的线虫病、螨和寄生性昆虫病，具有广谱、高效、安全等特点^[1-2]。近年来，除通过生物技术手段提高菌种的产素能力，以及生产工艺和制剂技术的改进来提高其活性外，对其母体结构的衍生化改造是开发阿维菌素类药物的重要途径之一。目前，以阿维菌素(1)为先导已衍生合成了数万种阿维菌素衍生物，其中甲氨基阿维菌素(emamectin，2)^[3]、伊维菌素(ivermectin，3)^[4]、埃珀利诺菌素(eprinomectin，4)^[5] (图式 1)等相继被商品化，这些衍生后的新化合物在防治范围、杀虫活性和对人畜及环境毒性等方面与阿维菌素相比有了进一步的改善。构效关系研究^[6-11]表明：在阿维菌素4"-位进行结构优化，有利于提高其杀虫活性和扩大杀虫谱，据此，笔者根据类同合成法和活性官能团拼接策略，在阿维菌素4"-位引入活性结构单元酰基硫脲和芳基脲，设计合成了两类新的阿维菌素衍生物，并分别初步测定了其对朱砂叶螨和甘蓝蚜的杀虫活性。

图式 1 阿维菌素及其部分衍生物结构式 Scheme1 Structures of abamectin and its derivatives

中间体4"-epi-氨基阿维菌素B1a (8)及目标化合物9a~9o和10a~10i的合成路线分别见图式 2和图式 3。

图式 2 中间体4''-epi-NH₂阿维菌素B1a (8)的合成路线 Scheme2 Synthesis route of intermediate 4''-epi-NH₂ avermectin B1a (8)

图式 3 目标化合物9a~9o和10a~10i的合成路线 Scheme3 Synthetic routes of compounds 9a-9o and 10a-10i

1 实验部分 1.1 仪器与试剂

X-4型数字显微熔点仪(温度未经校正)；Esquire 6000液相色谱-质谱联用仪；Brucker APEX Ⅱ质谱仪；热电TSQ Quantum LC/MS液相色谱-质谱联用仪；Bruke AM 400MHz超导核磁共振波谱仪。

阿维菌素B1a购于上海德默医药科技有限公司；0.054~0.075 mm粗孔型柱层析硅胶购自青岛海洋化工有限公司；自制薄层层析硅胶板，规格2.5 cm × 7.5 cm，GF254硅胶购自青岛海洋化工有限公司；羧甲基纤维素钠购自国药集团化学试剂有限公司；所有的无水溶剂均按标准方法预处理，其他试剂均为化学纯或分析纯。

1.2 化合物的合成 1.2.1 4"-epi-氨基阿维菌素B1a (8)的制备

参考文献[12-13]方法合成。先用TBDMSCl (叔丁基二甲基氯硅烷)将阿维菌素5-羟基保护，获得5-O-TBDMS avermectin B1a (5)；再在PhOPOCl₂/TEA/ DMSO反应体系下氧化，获得氧化物(6)。在化合物6中加入适量的醋酸铵与氰基硼氢化钠，将其还原为4"-epi-NH₂-5-O-TBDMS avermectin B1a (7)。将中间体7在冰浴条件下溶于含质量分数为1%的对甲苯磺酸的甲醇溶液中，60 ℃反应约2.5 h。产物经柱层析[(V (石油醚) : V (乙酸乙酯)=2 : 1)]分离得化合物4"-epi-氨基阿维菌素B1a (8)。

1.2.2 4"-脱氧-4"-酰基硫脲阿维菌素衍生物(9a~9o)的合成通法

参考文献[14-16]方法合成。将0.2 mmol化合物8溶于10 mL乙腈，在氮气保护下加入0.3 mmol不同取代的甲酰基异硫氰酸酯，室温搅拌2 h后，用氯仿稀释，过滤、水洗；每次用50 mL氯仿反萃取3次后合并有机相，用无水硫酸钠干燥，过滤，减压蒸馏后得黄色油状物，用适当体积比的石油醚和乙酸乙酯作洗脱剂，柱层析分离得到目标化合物9a~9o。

9a：产率：42%; m.p. 176~178 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 11.12 (d, 1H, J=10.0 Hz NHCS-H, ), 9.03 (s, 1H, NHCO-H), 7.85 (d, 2H, R-H2, H6, J=7.6 Hz), 7.64~7.61 (m, 1H, R-H4), 7.52 (t, 2H, R-H3, H5, J=7.2 Hz), 5.87~5.84 (m, 1H, H9), 5.78~5.73 (m, 3H, H23, H10, H11), 5.57~5.54 (m, 2H, H22, H3), 5.43 (br. s, 2H, H19, H1"), 4.98 (br. d, 1H, H15), 4.77 (s, 1H, H1′), 4.71~4.66 (m, 2H, H8a), 4.19 (d, 1H, H5, J=6.4Hz), 4.20~4.05 (m, 1H, 7-OH), 3.99~3.84 (m, 6H, H6, H13, H5′, H17, H5", H3′), 3.64~3.61 (m, 2H, H25, H3"), 3.53 (s, 3H, 3"-OCH₃), 3.49 (s, 1H, H2), 3.45 (s, 3H, 3′-OCH₃), 3.30~3.24 (m, 2H, H4′, H4"), 2.56~2.51 (m, 1H, H12), 2.38~2.14 (m, 6H, 5-OH, H16, H24, H2′), 2.03 (s, 1H, H20), 1.87 (s, 3H, 4-Me), 1.80~1.77 (m, 1H, H18), 1.61~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.27~2.23 (m, 6H, 6′-Me, 6"-Me), 1.17 (d, 3H, 12-Me), 0.96~0.87 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₆H₇₈N₂O₁₄S: C, 64.97; H, 7.59; N, 2.71. Found: C, 65.01; H, 7.55; N, 2.67. ESI-MS, m/z: 1 057.33[M+Na]⁺.

9b：产率：45%; m.p. 172~174 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 11.04 (d, 1H, NHCS-H, J=10.0 Hz), 8.97 (s, 1H, NHCO-H), 7.80 (d, 2H, R-H2, H6, J=8.4 Hz), 7.50 (d, 2H, R-H3, H5, J=8.4 Hz), 5.87~5.84 (m, 1H, H9), 5.78~5.73 (m, 3H, H23, H10, H11), 5.56~5.52 (m, 2H, H22, H3), 5.43 (br. s, 2H, H19, H1"), 4.99 (br. d, 1H, H15), 4.78~4.65 (m, 3H, H1′, H8a), 4.19 (d, 1H, H5, J=6.4 Hz), 4.05 (s, 1H, 7-OH), 3.99~3.94 (m, 2H, H6, H13), 3.88~3.81 (m, 4H, H5′, H17, H5", H3′), 3.64~3.61 (m, 2H, H25, H3"), 3.52 (s, 3H, 3"-OCH₃), 3.47 (s, 1H, H2), 3.44 (s, 3H, 3′-OCH₃), 3.32~3.23 (m, 2H, H4′, H4"), 2.56~2.51 (m, 1H, H12), 2.37~2.14 (m, 6H, 5-OH, H16, H24, H2′), 2.03 (s, 1H, H20), 1.88 (s, 3H, 4-Me), 1.79~1.76 (m, 1H, H18), 1.59~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.28~1.23 (m, 6H, 6′-Me, 6"-Me), 1.17 (d, 3H, 12-Me, J=6.8Hz), 0.96~0.85 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₆H₇₇ClN₂O₁₄S: C, 62.88; H, 7.26; N, 2.62. Found: C, 63.00; H, 7.24; N, 2.64. ESI-MS, m/z: 1 091.34[M+Na]⁺.

9c：产率：38%; m.p. 177~179 ℃; ¹H NMR (400 MHz, CDCl₃, δ: 10.99 (d, 1H, NHCS-H, J=9.2 Hz), 8.97 (s, 1H, NHCO-H), 7.86 (s, 1H, R-H2), 7.71 (d, 1H, R-H6, J=8.4 Hz), 7.60 (d, 1H, R-H4, J=8.0 Hz), 7.46 (t, 1H, R-H5, J=8.0 Hz), 5.87~5.84 (m, 1H, H9), 5.78~5.73 (m, 3H, H23, H10, H11), 5.56~5.52 (m, 2H, H22, H3), 5.43 (br. s, 2H, H19, H1"), 4.99 (br. d, 1H, H15), 4.77 (s, 1H, H1′), 4.69~4.67 (m, 2H, H8a), 4.19 (d, 1H, H5, J=6.0Hz), 4.04 (s, 1H, 7-OH), 3.99~3.94 (m, 2H, H6, H13), 3.88~3.84 (m, 4H, H5′, H17, H5", H3′), 3.64~3.61 (m, 2H, H25, H3"), 2.53 (s, 3H, 3"-OCH₃), 3.47 (s, 1H, H2), 3.45 (s, 3H, 3′-OCH₃), 3.30~3.24 (m, 2H, H4′, H4"), 2.56~2.51 (m, 1H, H12), 2.37~2.14 (m, 6H, 5-OH, H16, H24, H2′), 2.03 (s, 1H, H20), 1.88 (s, 3H, 4-Me), 1.79~1.76 (m, 1H, H18), 1.58~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.27~1.23 (m, 6H, 6′-Me, 6"-Me), 1.17 (d, 3H, 12-Me, J=7.2 Hz), 0.96~0.85 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₆H₇₇ClN₂O₁₄S: C, 62.88; H, 7.26; N, 2.62. Found: C, 63.01; H, 7.25; N, 2.63. ESI-MS, m/z: 1 091.38[M+Na]⁺.

9d：产率：48%; m.p. 189~191 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 11.06 (d, 1H, NHCS-H, J=9.6 Hz), 9.61 (d, 1H, NHCO-H, J=15.2 Hz), 8.08 (t, 1H, R-H6, J=7.2 Hz), 7.61 (dd, 1H, R-H4), 7.33 (t, 1H, R-H5, J=7.6 Hz), 7.24~7.21 (m, 1H, R-H3), 5.87~5.84 (m, 1H, H9), 5.78~5.73 (m, 3H, H23, H10, H11), 5.56~5.52 (m, 2H, H22, H3), 5.43 (br. s, 2H, H19, H1"), 4.98 (br. d, 1H, H15), 4.77 (s, 1H, H1′), 4.69~4.67 (m, 2H, H8a), 4.19 (d, 1H, H5, J=6.8 Hz), 4.04 (s, 1H, 7-OH), 3.99~3.94 (m, 2H, H6, H13), 3.86~3.81 (m, 4H, H5′, H17, H5", H3′), 3.64~3.61 (m, 2H, H25, H3"), 3.52 (s, 3H, 3"-OCH₃), 3.49 (d, 1H, H2, J=9.2 Hz), 3.45 (s, 3H, 3′-OCH₃), 3.30~3.24 (m, 2H, H4′, H4"), 2.56~2.51 (m, 1H, H12), 2.36~2.14 (m, 6H, 5-OH, H16, H24, H2′), 2.03 (s, 1H, H20), 1.88 (s, 3H, 4-Me), 1.79~1.76 (m, 1H, H18), 1.60~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.27~1.24 (m, 6H, 6′-Me, 6"-Me), 1.17 (d, 3H, 12-Me, J=6.8 Hz), 0.96~0.85 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₆H₇₇FN₂O₁₄S: C, 63.86; H, 7.37; N, 2.66; O, 21.27. Found: C, 63.90; H, 7.36; N, 2.65; O, 21.30. ESI-MS, m/z: 1 075.42[M+Na]⁺.

9e：产率：52%; m.p. 181~183 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 11.06 (d, 1H, NHCS-H, J=9.6 Hz), 8.95 (s, 1H, NHCO-H), 7.88 (dd, 2H, R-H2, H6, J=5.2, 8.4Hz), 7.20 (t, 2H, R-H3, H5, J=8.4 Hz), 5.87~5.84 (m, 1H, H9), 5.78~5.73 (m, 3H, H23, H10, H11), 5.56~5.52 (m, 2H, H22, H3), 5.43 (br. s, 2H, H19, H1"), 4.97 (br. d, 1H, H15), 4.77 (s, 1H, H1′), 4.69~4.67 (m, 2H, H8a), 4.19 (d, 1H, H5, J=6.4 Hz), 4.05 (s, 1H, 7-OH), 3.99~3.94 (m, 2H, H6, H13), 3.86~3.81 (m, 4H, H5′, H17, H5", H3′), 3.64~3.61 (m, 2H, H25, H3"), 3.52 (s, 3H, 3"-OCH₃), 3.47 (s, 1H, H2), 3.44 (s, 3H, 3′-OCH₃), 3.30~3.23 (m, 2H, H4′, H4"), 2.56~2.51 (m, 1H, H12), 2.36~2.14 (m, 6H, 5-OH, H16, H24, H2′), 2.03 (s, 1H, H20), 1.88 (s, 3H, 4-Me), 1.79~1.76 (m, 1H, H18), 1.58~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.25~1.23 (m, 6H, 6′-Me, 6"-Me), 1.17 (d, 3H, 12-Me, J=7.2 Hz), 0.96~0.87 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₆H₇₇FN₂O₁₄S: C, 63.86; H, 7.37; N, 2.66. Found: C, 63.89; H, 7.39; N, 2.66. ESI-MS, m/z: 1 075.29[M+Na]⁺.

9f：产率：54%; m.p. 157~159 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 11.02 (d, 1H, NHCS-H, J=10.0 Hz), 8.95 (s, 1H, NHCO-H), 7.72 (d, 2H, R-H2, H6, J=8.4 Hz), 7.66 (d, 2H, R-H3, H5, J=8.0 Hz), 5.87~5.84 (m, 1H, H9), 5.78~5.73 (m, 3H, H23, H10, H11), 5.56~5.51 (m, 2H, H22, H3), 5.43 (br. s, 2H, H19, H1"), 4.98~4.96 (m, 1H, H15), 4.78 (s, 1H, H1′), 4.69~4.67 (m, 2H, H8a), 4.29 (d, 1H, H5, J=6.8 Hz), 4.04 (s, 1H, 7-OH), 3.99~3.94 (m, 2H, H6, H13), 3.86~3.81 (m, 4H, H5′, H17, H5", H3′), 3.64~3.61 (m, 2H, H25, H3"), 3.52 (s, 3H, 3"-OCH₃), 3.48 (s, 1H, H2), 3.44 (s, 3H, 3′-OCH₃), 3.30~3.23 (m, 2H, H4′, H4"), 2.56~2.51 (m, 1H, H12), 2.36~2.14 (m, 6H, 5-OH, H16, H24, H2′), 2.03 (s, 1H, H20), 1.88 (s, 3H, 4-Me), 1.79~1.76 (m, 1H, H18), 1.57~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.25~1.23 (m, 6H, 6′-Me, 6"-Me), 1.17 (d, 3H, 12-Me, J=7.2 Hz), 0.95~0.85 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₆H₇₇BrN₂O₁₄S: C, 60.37; H, 6.97; N, 2.51. Found: C, 60.40; H, 6.96; N, 2.52. ESI-MS, m/z: 1 135.29[M+Na]⁺.

9g：产率：40%; m.p. 177~179 ℃; ¹H NMR (400MHz, CDCl₃), δ: 10.99 (d, 1H, NHCS-H, J=10.4 Hz), 8.96 (s, 1H, NHCO-H), 8.02 (s, 1H, R-H2), 7.75 (d, 2H, R-H4, H6, J=7.6 Hz), 7.39 (t, 1H, R-H5, J=8.0 Hz), 5.87~5.84 (m, 1H, H9), 5.78~5.73 (m, 3H, H23, H10, H11), 5.57~5.52 (m, 2H, H22, H3), 5.43 (br. s, 2H, H19, H1"), 4.98 (br. d, 1H, H15), 4.78~4.69 (m, 3H, H1′, H8a), 4.19 (d, 1H, H5, J=6.4 Hz), 4.05 (s, 1H, 7-OH), 3.99~3.94 (m, 2H, H6, H13), 3.86~3.82 (m, 4H, H5′, H17, H5", H3′), 3.63~3.60 (m, 2H, H25, H3"), 3.53 (s, 3H, 3"-OCH₃), 3.48 (s, 1H, H2), 3.46 (s, 3H, 3′-OCH₃), 3.30~3.24 (m, 2H, H4′, H4"), 2.56~2.51 (m, 1H, H12), 2.37~2.13 (m, 6H, 5-OH, H16, H24, H2′), 2.03 (s, 1H, H20), 1.88 (s, 3H, 4-Me), 1.79~1.76 (m, 1H, H18), 1.59~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.26~1.23 (m, 6H, 6′-Me, 6"-Me), 1.17 (d, 3H, 12-Me, J=7.2 Hz), 0.96~0.86 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₆H₇₇BrN₂O₁₄S: C, 60.37; H, 6.97; N, 2.51. Found: C, 60.38; H, 7.00; N, 2.54. ESI-MS, m/z: 1 135.43[M+Na]⁺.

9h：产率：41%; m.p. 166~168 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 9.08 (d, 1H, NHCS-H, J=10.0 Hz), 8.61 (s, 1H, NHCO-H), 7.77 (d, 2H, R-H2, H6, J=8.0 Hz), 7.29 (d, 2H, R-H3, H5, J=8.0 Hz), 5.87~5.84 (m, 1H, H9), 5.78~5.74 (m, 3H, H23, H10, H11), 5.55 (d, 1H, H22, J=10.0 Hz), 5.48 (br. s, 1H, H3), 5.42 (br. s, 2H, H19, H1"), 4.98 (br. d, 1H, H15), 4.77 (s, 1H, H1′), 4.78~4.69 (m, 2H, H8a), 4.30 (d, 1H, H5, J=6.0 Hz), 3.99~3.94 (m, 2H, H6, H13), 3.86~3.73 (m, 4H, H5′, H17, H5", H3′), 3.62~3.52 (m, 2H, H25, H3"), 3.49 (s, 3H, 3"-OCH₃), 3.45 (s, 3H, 3′-OCH₃), 3.27~3.14 (m, 2H, H4′, H4"), 2.56~2.51 (m, 1H, H12), 2.42 (s, 3H, R-Me), 2.38~2.03 (m, 7H, 5-OH, H16, H24, H2′, H18), 1.87 (s, 3H, 4-Me), 1.79~1.76 (m, 1H, H18), 1.59~1.46 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.28~1.16 (m, 9H, 6′-Me, 6"-Me, 12-Me), 0.98~0.79 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₇H₈₀N₂O₁₄S: C, 65.24; H, 7.68; N, 2.67. Found: C, 65.30; H, 7.68; N, 2.65. ESI-MS, m/z: 1 071.46 [M+Na]⁺.

9i：产率：46%; m.p. 184~185 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 10.91 (d, 1H, NHCS-H, J=9.6 Hz), 8.87 (s, 1H, NHCO-H), 7.70~7.66 (m, 2H, R-H3, H5), 7.17 (t, 1H, R-H4, J=4.4 Hz), 5.87~5.84 (m, 1H, H9), 5.78~5.73 (m, 3H, H23, H10, H11), 5.57~5.50 (m, 2H, H22, H3), 5.43 (br. s, 2H, H19, H1"), 4.98 (br. d, 1H, H15), 4.77 (s, 1H, H1′), 4.69~4.67 (m, 2H, H8a), 4.30 (d, 1H, H5, J=5.2 Hz), 3.99~3.94 (m, 2H, H6, H13), 3.87~3.80 (m, 4H, H5′, H17, H5", H3′), 3.62 (m, 2H, H25, H3"), 3.51 (s, 3H, 3"-OCH₃), 3.47 (s, 1H, H2), 3.44 (s, 3H, 3′-OCH₃), 3.30~3.23 (m, 2H, H4′, H4"), 2.52 (m, 1H, H12), 2.29~2.11 (m, 6H, 5-OH, H16, H24, H2′), 2.05 (s, 1H, H20), 1.88 (s, 3H, 4-Me), 1.79~1.75 (m, 1H, H18), 1.61~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.33~1.22 (m, 6H, 6′-Me, 6"-Me), 1.17 (d, 3H, 12-Me, J=6.8 Hz), 0.96~0.85 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₄H₇₆N₂O₁₅S₂: C, 62.28; H, 7.36; N, 2.69. Found: C, 62.40; H, 7.39; N, 2.70. ESI-MS, m/z: 1 063.47[M+Na]⁺.

9j：产率：30%; m.p. 179~180 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 10.96 (d, 1H, NHCS-H, J=9.6 Hz), 9.10 (s, 1H, NHCO-H), 9.04 (s, 1H, R-H2), 8.85 (d, 1H, R-H6, J=4.4 Hz), 8.16 (d, 1H, R-H4, J=8.0 Hz), 7.48 (dd, 1H, R-H5, J=4.8Hz, 8.4 Hz), 5.87~5.84 (m, 1H, H9), 5.78~5.73 (m, 3H, H23, H10, H11), 5.56~5.43 (m, 2H, H22, H3), 5.38 (br. s, 2H, H19, H1"), 4.98 (br. d, 1H, H15), 4.77 (s, 1H, H1′), 4.69~4.67 (m, 2H, H8a), 4.20 (d, 1H, H5, J=6.8 Hz), 4.05 (s, 1H, 7-OH), 3.99~3.94 (m, 2H, H6, H13), 3.88~3.82 (m, 2H, H5′, H17, H5", H3′), 3.65~3.60 (m, 2H, H25, H3"), 3.52 (s, 3H, 3"-OCH₃), 3.47 (s, 1H, H2), 3.45 (s, 3H, 3′-OCH₃), 3.30~3.24 (m, 2H, H4′, H4"), 2.53~2.49 (m, 1H, H12), 2.36~2.14 (m, 6H, 5-OH, H16, H24, H2′), 2.03 (s, 1H, H20), 1.87 (s, 3H, 4-Me), 1.78 (d, 1H, H18, J=13.6Hz), 1.60~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.26~1.19 (m, 6H, 6′-Me, 6"-Me), 1.17 (d, 3H, 12-Me, J=6.8 Hz), 0.96~0.87 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₅H₇₇N₃O₁₄S: C, 63.75; H, 7.49; N, 4.05. Found: C, 63.80; H, 7.46; N, 4.00. ESI-MS, m/z: 1 058.44[M+Na]⁺.

9k：产率：45%; m.p. 168~170 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 10.85 (d, 1H, NHCO-H, J=9.6 Hz), 9.14 (s, 1H, NHCS-H), 7.58 (s, 1H, R-H5), 7.33 (d, 1H, R-H3, J=3.2 Hz), 6.60 (s, 1H, R-H4), 5.87~5.84 (m, 1H, H9), 5.78~5.72 (m, 3H, H23, H10, H11), 5.56~5.50 (m, 2H, H22, H3), 5.43 (br. s, 2H, H19, H1"), 4.97 (br. d, 1H, H15), 4.76 (s, 1H, H1′), 4.69~4.67 (m, 2H, H8a), 4.17 (d, 1H, H5, J=6.4 Hz), 4.04 (s, 1H, 7-OH), 3.99~3.94 (m, 2H, H6, H13), 3.87~3.79 (m, 4H, H5′, H17, H5", H3′), 3.65~3.60 (m, 2H, H25, H3"), 3.51 (s, 3H, 3"-OCH₃), 3.47 (s, 1H, H2), 3.44 (s, 3H, 3′-OCH₃), 3.30~3.23 (m, 2H, H4′, H4"), 2.53~2.49 (m, 1H, H12), 2.36~2.12 (m, 6H, 5-OH, H16, H24, H2′), 2.05 (s, 1H, H20), 1.88 (s, 3H, 4-Me), 1.76~1.74 (m, 1H, H18), 1.58~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.25~1.22 (m, 6H, 6′-Me, 6"-Me), 1.17 (d, 3H, 12-Me, J=6.8 Hz), 0.95~0.87 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₄H₇₆N₂O₁₅S: C, 63.26; H, 7.47; N, 2.73. Found: C, 63.40; H, 7.50; N, 2.73. ESI-MS, m/z: 1 047.29[M+Na]⁺.

9l：产率：50%; m.p. 176~178 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 11.19 (d, 1H, NHCS-H, J=10.0 Hz), 9.19 (s, 1H, NHCO-H), 8.40 (s, 1H, R-H1), 7.98~7.86 (m, 4H, R-H3, H4, H5, H8), 7.67~7.59 (m, 2H, R-H6, H7), 5.87~5.84 (m, 1H, H9), 5.79~5.73 (m, 3H, H23, H10, H11), 5.57~5.55 (m, 2H, H22, H3), 5.43 (br. s, 2H, H19, H1"), 4.98 (br. d, 1H, H15), 4.78 (s, 1H, H1′), 4.69~4.67 (m, 2H, H8a), 4.30 (d, 1H, H5, J=6.0 Hz), 4.08~4.03 (m, 1H, 7-OH), 3.99~3.95 (m, 2H, H6, H13), 3.87~3.83 (m, 4H, H5′, H17, H5", H3′), 3.64~3.61 (m, 2H, H25, H3"), 3.54 (s, 3H, 3"-OCH₃), 3.50 (s, 1H, H2), 3.45 (s, 3H, 3′-OCH₃), 3.27 (t, 2H, H4′, H4", J=8.8 Hz), 2.53~2.51 (m, 1H, H12), 2.36~2.14 (m, 6H, 5-OH, H16, H24, H2′), 2.03 (s, 1H, H20), 1.88 (s, 3H, 4-Me), 1.80~1.77 (m, 1H, H18), 1.62~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.28~1.25 (m, 6H, 6′-Me, 6"-Me), 1.18(d, 3H, 12-Me, J=6.8 Hz), 0.96~0.87 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₆₀H₈₀N₂O₁₄S: C, 66.40; H, 7.43; N, 2.58. Found: C, 66.54; H, 7.40; N, 2.55. ESI-MS, m/z: 1 107.42 [M+Na]⁺.

9m：产率：30%; m.p. 175~177 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 10.92 (d, 1H, NHCS-H, J=10.0 Hz), 8.45 (s, 1H, NHCO-H), 5.87~5.84 (m, 1H, H9), 5.78~5.72 (m, 3H, H23, H10, H11), 5.55 (d, 1H, H22, J=10.0 Hz), 5.48 (br. d, 1H, H3), 5.42 (br. s, 2H, H19, H1"), 4.99~4.95 (m, 1H, H15), 4.77 (s, 1H, H1′), 4.69~4.67 (m, 2H, H8a), 4.29~4.26 (m, 1H, H5), 4.08~4.03 (m, 1H, 7-OH), 3.98~3.94 (m, 2H, H6, H13), 3.88~3.76 (m, 4H, H5′, H17, H5", H3′), 3.61~3.58 (m, 2H, H25, H3"), 3.50 (s, 3H, 3"-OCH₃), 3.47 (s, 1H, H2), 3.42 (s, 3H, 3′-OCH₃), 3.29 (s, 1H, H4"), 3.23 (t, 1H, H4′, J=8.8 Hz), 2.56~2.51 (m, 1H, H12), 2.36~2.14 (m, 7H, 5-OH, H16, H24, H2′, R-H1), 2.03 (s, 1H, H20), 1.93~1.77 (m, 3H, H18, R-H2, H6), 1.67~1.42 (m, 17H, H20, H26, H27, 14-Me, H2", R-H2, H6, R-H3, R-H4, R-H5), 1.28~1.26 (m, 6H, 6′-Me, 6"-Me), 1.18~0.83 (m, 13H, 12-Me, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₆H₈₄N₂O₁₄S: C, 64.59; H, 8.13; N, 2.69. Found: C, 64.70; H, 8.15; N, 2.75. ESI-MS, m/z: 1 063.47 [M+Na]⁺.

9n：产率：35%; m.p. 183~185 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 10.91 (d, 1H, NHCS-H, J=10.0 Hz), 8.53 (s, 1H, NHCO-H), 5.87~5.84 (m, 1H, H9), 5.78~5.72 (m, 3H, H23, H10, H11), 5.57 (d, 1H, H22, J=2.0 Hz), 5.54~5.48 (m, 3H, H3, H19, H1"), 4.99~4.95 (m, 1H, H15), 4.77 (s, 1H, H1′), 4.69~4.67 (m, 2H, H8a), 4.29~4.26 (m, 1H, H5), 4.05 (s, 1H, 7-OH), 3.98~3.93 (m, 2H, H6, H13), 3.88~3.76 (m, 4H, H5′, H17, H5", H3′), 3.64~3.58 (m, 2H, H25, H3"), 3.49 (s, 3H, 3"-OCH₃), 3.47 (s, 1H, H2), 3.43 (s, 3H, 3′-OCH₃), 3.29 (s, 1H, H4"), 3.23 (t, 1H, H4′, J=8.8 Hz), 2.55~2.51 (m, 1H, H12), 2.36~2.14 (m, 6H, 5-OH, H16, H24, H2′), 2.14 (s, 3H, R-Me), 2.05 (s, 1H, H20), 1.87 (s, 3H, 4-Me), 1.77 (d, 1H, H18, J=12.8 Hz), 1.58~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.28~1.15 (m, 9H, 6′-Me, 6"-Me, 12-Me), 0.95~0.83 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₁H₇₆N₂O₁₄S: C, 62.94; H, 7.87; N, 2.88. Found: C, 62.97; H, 7.88; N, 2.95. ESI-MS, m/z: 995.60[M+Na]⁺.

9o：产率：32%; m.p. 185~187 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 10.91 (d, 1H, NHCS-H, J=10.0 Hz), 8.51 (s, 1H, NHCO-H), 5.87~5.84 (m, 1H, H9), 5.78~5.72 (m, 3H, H23, H10, H11), 5.55 (d, 1H, H22, J=10.0 Hz), 5.49 (br. s, 1H, H3), 5.43 (br. s, 2H, H19, H1"), 4.98 (br. d, 1H, H15), 4.76 (s, 1H, H1′), 4.69~4.65 (m, 2H, H8a), 4.14 (d, 1H, H5, J=7.2 Hz), 4.05 (s, 1H, 7-OH), 3.98~3.93 (m, 2H, H6, H13), 3.86~3.77 (m, 4H, H5′, H17, H5", H3′), 3.61~3.58 (m, 2H, H25, H3"), 3.50 (s, 3H, 3"-OCH₃), 3.47 (s, 1H, H2), 3.42 (s, 3H, 3′-OCH₃), 3.29 (s, 1H, H4"), 3.23 (t, 1H, H4′, J=9.2Hz), 2.60 (t, 1H, R-H1, J=7.6Hz), 2.56~2.51 (m, 1H, H12), 2.37~2.11 (m, 6H, 5-OH, H16, H24, H2′), 1.91~1.70 (m, 6H, 4-Me, H18, R-H2, H5), 1.66~1.42 (m, 15H, H20, H26, H27, 14-Me, H2", R-H2, H5, H3, H4), 1.28~1.24 (m, 9H, 6′-Me, 6"-Me, 12-Me), 0.99~0.86 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₅H₈₂N₂O₁₄S: C, 64.30; H, 8.05; N, 2.73. Found: C, 64.40; H, 8.10; N, 2.79. ESI-MS, m/z: 1 049.43 [M+Na]⁺.

1.2.3 4"-脱氧-4"-芳基脲阿维菌素衍生物(化合物10a~10i)的合成通法

参考文献[17-18]方法合成。将0.2 mmol化合物8溶于10 mL干燥的二氯甲烷中，在氮气保护下加入0.4 mmol不同取代的异氰酸酯，室温搅拌2 h后，用二氯甲烷稀释，反应液依次用水(15 mL × 3)和饱和食盐水(20 mL)洗涤，每次用50 mL二氯甲烷反萃取2~3次后合并有机相，无水硫酸镁干燥，过滤，浓缩后用适当体积比的石油醚和乙酸乙酯作洗脱剂，柱层析分离得到目标化合物10a~10i。

10a：产率：45%; m.p. 160~162 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 7.33 (d, 2H, R-H3, H6, J=8.0 Hz), 7.21 (s, 1H, Ar-NH), 6.94 (t, 2H, R-H4, H5, J=7.6 Hz), 5.87~5.84 (m, 1H, H9), 5.78~5.72 (m, 3H, H23, H10, H11), 5.55 (d, 1H, H22, J=8.4 Hz), 5.42 (br. s, 3H, H3, H19, H1"), 4.98 (br. d, 1H, H15), 4.92 (d, 1H, -NH, J=8.8 Hz), 4.78 (s, 1H, H1′), 4.69~4.67 (m, 2H, H8a), 4.29 (d, 1H, H5, J=6.8 Hz), 4.05 (s, 1H, 7-OH), 3.98~3.93 (m, 2H, H6, H13), 3.87~3.74 (m, 4H, H5′, H17, H5", H3′), 3.66~3.61 (m, 2H, H25, H3"), 3.46 (s, 3H, 3"-OCH₃), 3.45 (s, 3H, 3′-OCH₃), 3.30 (s, 1H, H4"), 3.23 (t, 1H, H4′, J=8.4 Hz), 2.56~2.51 (m, 1H, H12), 2.36~2.02 (m, 7H, 5-OH, H16, H24, H2′, H20), 1.88 (s, 3H, 4-Me), 1.78 (d, 1H, H18, J=9.6 Hz), 1.68~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.25~1.21 (m, 6H, 6′-Me, 6"-Me), 1.17 (d, 3H, 12-Me, J=6.8 Hz), 0.95~0.87 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₅H₇₇ClN₂O₁₄: C, 64.41; H, 7.57; N, 2.73. Found: C, 64.45; H, 7.47; N, 2.73. ESI-MS，m/z: 1 047.55 [M+Na]⁺.

10b：产率：50%; m.p. 168~170 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 7.22 (d, 2H, R-H2, H6, J=8.0 Hz), 7.11 (d, 2H, H3, H5, J=5.6 Hz), 6.80 (s, 1H, Ar-NH), 5.87~5.84 (m, 1H, H9), 5.78~5.73 (m, 3H, H23, H10, H11), 5.56 (d, 1H, H22, J=10.0 Hz), 5.42~5.36 (br. d, 3H, H3, H19, H1"), 4.98 (br. d, 1H, H15), 4.91 (d, 1H, -NH, J=9.2 Hz), 4.77 (s, 1H, H1′), 4.69~4.67 (m, 2H, H8a), 4.29 (d, 1H, H5, J=7.2 Hz), 4.06 (s, 1H, 7-OH), 3.98~3.93 (m, 2H, H6, H13), 3.86~3.72 (m, 4H, H5′, H17, H5", H3′), 3.66~3.61 (m, 2H, H25, H3"), 3.45 (s, 3H, 3"-OCH₃), 3.43 (s, 3H, 3′-OCH₃), 3.30 (s, 1H, H2), 3.20 (t, 1H, H4", J=8.8 Hz), 2.56~2.51 (m, 1H, H12), 2.37~2.20 (m, 6H, 5-OH, H16, H24, H2′), 2.05 (s, 1H, H20), 1.87 (s, 3H, 4-Me), 1.77 (d, 1H, H18, J=10.4 Hz), 1.60~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.25~1.21 (m, 6H, 6′-Me, 6"-Me), 1.16 (d, 3H, 12-Me, J=6.4 Hz), 0.95~0.88 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₅H₇₇FN₂O₁₄: C, 65.46; H, 7.69; N, 2.78. Found: C, 64.55; H, 7.74; N, 2.76. ESI-MS, m/z: 1 031.44[M+Na]⁺.

10c：产率：38%; m.p. 178~180 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 7.17 (d, 2H, R-H2, H6, J=8.4 Hz), 7.11 (d, 2H, R-H3, H5, J=2.4 Hz), 6.80 (s, 1H, Ar-NH), 5.85 (br. d, 1H, H9), 5.78~5.71 (m, 3H, H23, H10, H11), 5.60~5.54 (m, 2H, H22, H3), 5.38~5.32 (m, 2H, H19, H1"), 5.05~4.99 (m, 2H, H15, -NH), 4.76 (br. s, 1H, H1′), 4.70~4.59 (m, 2H, H8a), 3.97~3.92 (m, 3H, 7-OH, H6, H13), 3.85~3.70 (m, 4H, 4H, H5′, H17, H5", H3′), 3.63~3.60 (m, 2H, H25, H3"), 3.45 (s, 3H, 3"-OCH₃), 3.42 (s, 3H, 3′-OCH₃), 3.30 (s, 1H, H2), 3.18 (t, 1H, H4", J=9.2 Hz), 2.56~2.51 (m, 1H, H12), 2.36~2.02 (m, 9H, 5-OH, H16, H24, H2′, R-Me), 2.03 (s, 1H, H20), 1.81 (s, 3H, 4-Me), 1.76~1.42 (m, 10H, H18, H20, H26, H27, 14-Me, H2"), 1.26~1.17 (m, 9H, 6′-Me, 6"-Me, 12-Me), 0.95~0.79 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₆H₈₀N₂O₁₄: C, 66.91; H, 8.02; N, 2.79. Found: C, 66.96; H, 8.00; N, 2.83. ESI-MS，m/z: 1 027.56[M+Na]⁺.

10d：产率：40%; m.p. 173~175 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 7.02~6.93 (m, 2H, R-H2, H6), 6.91~6.84 (m, 2H, R-H3, H5), 5.87~5.84 (m, 1H, H9), 5.78~5.72 (m, 3H, H23, H10, H11), 5.55 (d, 1H, H22, J=8.4 Hz), 5.43~5.38 (m, 3H, H3, H19, H1"), 4.99~4.95 (m, 2H, H15, -NH), 4.77 (s, 1H, H1′), 4.69~4.67 (m, 2H, H8a), 4.29 (d, 1H, H5, J=6.8 Hz), 4.07 (s, 1H, 7-OH), 3.98~3.93 (m, 2H, H6, H13), 3.86~3.72 (m, 7H, H5′, H17, H5", H3′, R-OMe), 3.66~3.60 (m, 2H, H25, H3"), 3.46 (s, 3H, 3"-OCH₃), 3.45 (s, 3H, 3′-OCH₃), 3.30 (s, 1H, H2), 3.22 (t, 1H, H4", J=8.8 Hz), 2.56~2.51 (m, 1H, H12), 2.42~2.18 (m, 7H, 5-OH, H16, H24, H2′, H20), 2.05 (s, 1H, H20), 1.87 (s, 3H, 4-Me), 1.78 (d, 1H, H18, J=8.4 Hz), 1.67~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.28~1.16 (m, 9H, 6′-Me, 6"-Me, 12-Me), 0.95~0.87 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₆H₈₀N₂O₁₅: C, 65.86; H, 7.90; N, 2.74. Found: C, 65.90; H, 7.91; N, 2.70. ESI-MS, m/z: 1 021.11 [M+H]⁺.

10e：产率：45%; m.p. 166~168 ℃; ¹H NMR (400MHz, CDCl₃), δ: 7.39~7.30 (m, 2H, R-H2, H6), 7.19~7.17 (m, 1H, H4), 7.10~7.06 (m, 2H, R-H3, H5), 6.86 (s, 1H, Ar-NH), 5.89~5.86 (m, 1H, H9), 5.82~5.76 (m, 3H, H23, H10, H11), 5.59 (d, 1H, H22, J=10.0 Hz), 5.46~5.41 (m, 3H, H3, H19, H1"), 5.01 (m, 1H, H15), 4.93 (s, 1H, -NH), 4.80 (s, 1H, H1′), 4.76~4.68 (m, 2H, H8a), 4.33~4.27 (m, 1H, H5), 4.03 (s, 1H, 7-OH), 3.97~3.90 (m, 2H, H6, H13), 3.88~3.70 (m, 4H, H5′, H17, H5", H3′), 3.67~3.63 (m, 2H, H25, H3"), 3.49 (s, 3H, 3"-OCH₃), 3.47 (s, 3H, 3′-OCH₃), 3.30 (s, 1H, H2), 3.24 (t, 1H, H4", J=8.8 Hz), 2.56~2.51 (m, 1H, H12), 2.47~2.02 (m, 7H, 5-OH, H16, H24, H2′, H20), 1.91 (s, 3H, 4-Me), 1.81 (d, 1H, H18, J=12.0 Hz), 1.68~1.46 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.28~1.19 (m, 9H, 6′-Me, 6"-Me, 12-Me, ), 0.99~0.90 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₅H₇₈N₂O₁₄: C, 66.64; H, 7.93; N, 2.83. Found: C, 66.70; H, 7.95; N, 2.83. ESI-MS, m/z: 1 013.58[M+Na]⁺.

10f：产率：36%; m.p. 174~176 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 7.44 (s, 1H, R-H2), 7.21~7.17 (m, 2H, R-H5, H6), 6.98 (d, 1H, H4, J=6.4 Hz), 5.88~5.84 (m, 1H, H9), 5.78~5.72 (m, 3H, H23, H10, H11), 5.55 (d, 1H, H22, J=7.6 Hz), 5.42 (br. d, 3H, H3, H19, H1"), 5.10 (br. d, 1H, H15), 4.97 (d, 1H, -NH, J=6.0 Hz), 4.78 (s, 1H, H1′), 4.73~4.69 (m, 2H, H8a), 4.34~4.30 (m, 1H, H5), 4.07 (s, 1H, 7-OH), 3.98~3.93 (m, 2H, H6, H13), 3.87~3.74 (m, 4H, H5′, H17, H5", H3′), 3.66~3.60 (m, 2H, H25, H3"), 3.46 (s, 3H, 3"-OCH₃), 3.44 (s, 3H, 3′-OCH₃), 3.30 (s, 1H, H2), 3.22 (t, 1H, H4", J=8.8 Hz), 2.56~2.51(m, 1H, H12), 2.36~2.18 (m, 6H, 5-OH, H16, H24, H2′), 2.05 (s, 1H, H20), 1.88 (s, 3H, 4-Me), 1.78 (d, 1H, H18, J=10.4 Hz), 1.65~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.25~1.20 (m, 6H, 6′-Me, 6"-Me), 1.16 (d, 3H, 12-Me, J=6.8 Hz), 0.95~0.85 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₅H₇₇ClN₂O₁₄: C, 64.41; H, 7.57; N, 2.73. Found: C, 64.50; H, 7.53; N, 2.75. ESI-MS, m/z: 1 047.55 [M+Na]⁺.

10g：产率：52%; m.p. 177~179 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 7.30 (d, 2H, R-H2, H6, J=8.0 Hz), 7.21 (d, 2H, H3, H5, J=8.8 Hz), 6.77 (s, 1H, Ar-NH), 5.87~5.84 (m, 1H, H9), 5.78~5.71 (m, 3H, H23, H10, H11), 5.59~5.54 (m, 3H, H22, H3, H1"), 5.38~5.36 (m, 1H, H19), 4.97 (br. d, 1H, H15), 4.88 (d, 1H, -NH), 4.76 (s, 1H, H1′), 4.71~4.60 (m, 2H, H8a), 4.08~3.92 (m, 3H, 7-OH, H6, H13), 3.86~3.71 (m, 7H, H5′, H17, H5", H3′, R-OMe), 3.68~3.60 (m, 2H, H25, H3"), 3.45 (s, 3H, 3"-OCH₃), 3.42 (s, 3H, 3′-OCH₃), 3.34 (s, 1H, H2), 3.17 (t, 1H, H4", J=8.4 Hz), 2.56~2.51 (m, 1H, H12), 2.29~2.21 (m, 6H, 5-OH, H16, H24, H2′), 2.05 (s, 1H, H20), 1.81 (s, 3H, 4-Me), 1.76~1.42 (m, 10H, H18, H20, H26, H27, 14-Me, H2"), 1.28~1.17 (m, 9H, 6′-Me, 6"-Me, 12-Me), 0.95~0.85 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₆H₈₀N₂O₁₅: C, 65.86; H, 7.90; N, 2.74. Found: C, 65.90; H, 7.92; N, 2.72. ESI-MS, m/z: 1 043.45[M+H]⁺.

10h：产率：50%; m.p. 169~171 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 8.31 (s, 1H, R-H1), 7.95~7.86 (m, 4H, R-H3, H4, H5, H8), 7.59~7.53 (m, 2H, R-H6, H7), 6.44 (d, 1H, Ar-NH, J=10.0 Hz), 5.89~5.83 (m, 1H, H9), 5.78~5.73 (m, 3H, H23, H10, H11), 5.57~5.52 (m, 2H, H22, H3), 5.43 (br. s, 2H, H19, H1"), 4.99 (br. d, 1H, H15), 4.79 (s, 1H, -NH), 4.74~4.69 (m, 3H, H1′, H8a), 4.21 (d, 1H, H5, J=6.0 Hz), 4.05 (s, 1H, 7-OH), 3.99~3.90 (m, 2H, H6, H13), 3.88~3.79 (m, 4H, H5′, H17, H5", H3′), 3.69~3.64 (m, 2H, H25, H3"), 3.46 (s, 3H, 3"-OCH₃), 3.42 (s, 3H, 3′-OCH₃), 3.30~3.24 (m, 3H, H2, H4"), 2.56~2.51 (m, 1H, H12), 2.30~2.03 (m, 7H, 5-OH, H16, H24, H2′, H20), 1.88 (s, 3H, 4-Me), 1.78 (d, 1H, H18, J=11.6 Hz), 1.59~1.39 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.27~1.21 (m, 6H, 6′-Me, 6"-Me), 1.18 (d, 3H, 12-Me, J=6.4 Hz), 0.96~0.88 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₉H₈₀N₂O₁₄: C, 68.05; H, 7.74; N, 2.69. Found: C, 68.10; H, 7.72; N, 2.70. ESI-MS, m/z: 1 048.61 [M+H]⁺.

10i：产率：48%; m.p. 175~177 ℃; ¹H NMR (400 MHz, CDCl₃), δ: 7.38 (d, 2H, R-H2, H6, J=8.4 Hz), 7.22 (d, 2H, R-H3, H5, J=8.4 Hz), 5.87~5.82 (m, 1H, H9), 5.78~5.72 (m, 3H, H23, H10, H11), 5.55 (d, 1H, H22, J=9.6 Hz), 5.43~5.38 (m, 3H, H3, H19, H1"), 4.99~4.96 (m, 2H, H15, Ar-H), 4.77 (s, 1H, H1′), 4.69~4.67 (m, 2H, H8a), 4.30 (d, 1H, H5, J=6.4 Hz), 4.07 (s, 1H, 7-OH), 3.98~3.93 (m, 2H, H6, H13), 3.86-3.73 (m, 4H, H5′, H17, H5", H3′), 3.66~3.62 (m, 2H, H25, H3"), 3.45 (s, 3H, 3"-OCH₃), 3.44 (s, 3H, 3′-OCH₃), 3.30 (s, 1H, H2), 3.23 (t, 1H, H4", J=8.8 Hz), 2.56~2.51 (m, 1H, H12), 2.40~2.18 (m, 6H, 5-OH, H16, H24, H2′), 2.05 (s, 1H, H20), 1.88 (s, 3H, 4-Me), 1.77 (d, 1H, H18, J=11.2 Hz), 1.65~1.42 (m, 9H, H20, H26, H27, 14-Me, H2"), 1.25~1.21 (m, 6H, 6′-Me, 6"-Me), 1.18 (d, 3H, 12-Me, J=8.8 Hz), 0.97~0.85 (m, 10H, 27-Me, 24-Me, 26-Me, H18ax). Anal. Calcd For C₅₅H₇₇BrN₂O₁₄: C, 61.73; H, 7.25; N, 2.62. Found: C, 61.77; H, 7.23; N, 2.64. ESI-MS, m/z: 1 091.41[M+Na]⁺.

1.3 生物活性测定 1.3.1 对朱砂叶螨的杀虫活性

朱砂叶螨Tetranychus cinnabarinus雌成螨，采自甘肃省农业科学院田间的黄豆苗上。参照玻片浸渍法^[19]并加以改进。将阿维菌素衍生物在预试验基础上用水稀释成5个系列质量浓度药液，以清水作对照。挑选大小一致、体色鲜艳、行动活泼的雌成螨，将其背部粘在玻璃片一端，每片3行，每行10头。在温度(25±1) ℃、相对湿度85%左右的生化培养箱中放置4 h后，用双目镜观察，剔除死亡或不活泼个体。将带螨玻片的一端浸入溶液中，轻轻摇动5 s后取出，迅速吸干螨体及其周围多余药液。置于上述生化培养箱中，24 h后用双目镜检查结果。化合物各浓度试验平行进行3次，结果取平均值。

1.3.2 对甘蓝蚜的杀虫活性

甘蓝蚜Brevicoryne brassicae成虫，采自甘肃省农业科学院田间的油菜上。参照点滴法^[20]，先将化合物溶解在适量丙酮中，配成1 g/L的药液，再用含质量分数为0.1%的吐温-20的水溶液稀释成不同浓度。每个浓度设3个重复，每重复为1个培养皿。用微量点滴器点滴豆蚜背部，每虫点滴量为0.03 μL。置于24~25 ℃、相对湿度85%左右的生化培养箱中，24 h后检测死亡率。对照组点滴丙酮单独测试。化合物各浓度试验平行进行3次，结果取平均值。

1.3.3 数据分析

用Abbott公式对处理组死亡率进行校正，试验结果采用SPSS统计软件(版本13.0)进行分析，计算致死中浓度(LC₅₀)。

2 结果与讨论 2.1 对朱砂叶螨的杀螨活性

结果(表 1)表明：所有目标化合物对朱砂叶螨的毒杀活性(LC₅₀值0.100~0.842 μmol/L)均低于阿维菌素B1a (LC₅₀值0.013 μmol/L)；两个系列衍生物的杀螨活性相当，表明(硫)脲官能团本身氧原子与硫原子的差异及酰基的引入对朱砂叶螨的杀螨活性影响不明显。

表 1 阿维菌素芳基脲及酰基硫脲类衍生物对朱砂叶螨和甘蓝蚜毒杀活性 Table 1 Insecticidal activity of abamectin aryl urea and thiourea derivatives against Teranychus reinnabarinus and Brenicoryne brassicae

2.2 对甘蓝蚜的杀虫活性

结果(表 1)表明：大部分目标化合物对甘蓝蚜的毒杀活性优于母体化合物阿维菌素(LC₅₀=52.2 μmol/L)，表现出了强烈的杀蚜虫活性，表明脲官能团的引入对于甘蓝蚜虫的选择性增高。其中，化合物9h (1.71 μmol/L)、9o (1.13 μmol/L)、10a (5.72 μmol/L)是最具代表性的3个化合物，优于阿维菌素B1a 1~2个数量级。本结果表明，通过在阿维菌素4"-位引入酰基硫脲或芳基脲活性结构单元在防治蚜虫方面具有很大潜质。

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