含1, 2, 3-三氮唑结构的1, 5-苯并硫氮杂(艹卓)的合成及其抑真菌活性

王冉冉 王岩 边彦青 张萍

引用本文: 王冉冉, 王岩, 边彦青, 张萍. 含1, 2, 3-三氮唑结构的1, 5-苯并硫氮杂(艹卓)的合成及其抑真菌活性[J]. 有机化学, 2020, 40(2): 398-407. doi: 10.6023/cjoc201907056 shu
Citation:  Wang Ranran, Wang Yan, Bian Yanqing, Zhang Ping. Synthesis and Antifungal Activity of 1, 5-Benzothiazepines Containing 1, 2, 3-Triazole[J]. Chinese Journal of Organic Chemistry, 2020, 40(2): 398-407. doi: 10.6023/cjoc201907056 shu

含1, 2, 3-三氮唑结构的1, 5-苯并硫氮杂(艹卓)的合成及其抑真菌活性

    通讯作者: 张萍, zhangpingp@sina.com
  • 基金项目:

    河北省自然科学基金(No.B2017205100)资助项目

摘要: 设计合成了三类含1,2,3-三氮唑结构的1,5-苯并硫氮杂(艹卓)化合物3-(1H-1,2,3-三氮唑)-4-芳基-2,5-二氢-1,5-苯并硫氮杂(艹卓)(5a~5f)、3-(2H-1,2,3-三氮唑)-4-芳基-2,3-二氢-1,5-苯并硫氮杂(艹卓)(6a~6f)和3-(1H-1,2,3-三氮唑)-4-芳基-2,3,4,5-四氢-1,5-苯并硫氮杂(艹卓)(7a~7f).研究了中间体及目标产物的合成条件,分离出其中两个副产物并进行了结构确定.目标产物的抑真菌活性测试表明,化合物5a~5f对真菌具有良好的抑制作用,对新生隐球菌的抑制效果尤为突出.初步抑真菌构效关系研究表明,1H-1,2,3-三氮唑环和C=C双键是化合物5a~5f抑真菌活性的关键官能团.

English

  • 杂环化合物在生物化学和药物开发中占有重要的地位[1, 2], 据统计, 目前临床上使用的药物90%以上属于杂环化合物, 因此一个多世纪以来, 杂环化合物成为了有机合成研究的最大领域之一[3, 4].近20年来, 含硫和氮的杂环化合物特别是苯并硫氮杂䓬, 因其广谱的生物活性[5~7]引起越来越多研究者的兴趣. 1, 5-苯并硫氮杂䓬是苯并硫氮杂䓬的重要分支, 含该骨架的化合物在临床上可用于心脑血管疾病和精神类疾病的治疗, 如抗心绞痛和高血压的地尔硫卓[8]和克仑硫卓[9], 抗焦虑和抑郁的硫西新[10]和喹硫平[11].除此之外, 该类化合物还具有抗肿瘤[12]、抗人免疫缺陷病毒(HIV)[13]及抗炎[14]等作用, 且可用作肌肉松弛剂[15]和细胞毒类药物[16].近年来, 1, 5-苯并硫氮杂䓬在抑菌方面展现出的活性再一次引起了人们的关注, 如Satbir等[17]报道的含有茚环的1, 5-苯并硫氮杂䓬对大肠杆菌、白色念珠菌及黑曲霉菌的抑制作用均高于相应的对照药物, 张静等[18]合成的含氟取代的1, 5-苯并硫氮杂䓬对新生隐球菌有较强的抑制作用.三氮唑是含有三个氮原子的五元杂环化合物, 分为1, 2, 3-三氮唑和1, 2, 4-三氮唑两类.其中1, 2, 3-三氮唑具有较好的稳定性, 对氧化和酶降解不敏感, 且含有1, 2, 3-三氮唑的化合物具有抗肿瘤[19]、抗炎[20]、抗结核[21]、抗病毒[22]及抗真菌[23]等多种生物活性, 近年来受到药物化学家的持续关注, 目前已有多个1, 2, 3-三氮唑类化合物处于临床前或临床评价阶段[24].

    本课题组[25]利用活性拼接原理合成了含1, 2, 4-三氮唑的1, 5-苯并硫氮杂䓬化合物, 该类化合物对新生隐球菌和白色念珠菌的抑制活性均超过了对照药物氟康唑, 具有潜在的临床应用价值.为了进一步寻找高效抑真菌的活性化合物, 鉴于1, 2, 3-三氮唑的结构特点和生理活性, 将1, 2, 4-三氮唑置换为1, 2, 3-三氮唑, 设计并合成了三类含1, 2, 3-三氮唑结构的1, 5-苯并硫氮杂䓬化合物(Scheme 1), 测试了目标化合物对新生隐球菌标准株(C. neoformans stand)、新生隐球菌临床株(C. neoformans clinical)和白色念珠菌(C. albicans)的抑制作用, 和1, 2, 4-三氮唑取代的1, 5-苯并硫氮杂䓬相对比, 进行初步的构效关系分析, 以期为此类化合物的深入研究提供参考和借鉴.

    图式 1

    图式 1.  化合物的合成路线5a~5f、6a~6f7a~7f
    Scheme 1.  Synthetic route of compounds 5a~5f、6a~6f and 7a~7f

    化合物2a~2f2'a~2'f的合成参照文献[26]方法, 用三乙胺代替文献中的氢化钠作缚酸剂, 在乙腈中回流反应1 h, 得到目标产物.在1, 2, 3-三氮唑的平衡中(Eq. 1), 2H-1, 2, 3-三氮唑是主要组分[27], 其环上N1和N3原子的亲核性(产物为2a~2f)强于N2原子(产物为2'a~2'f); 1H-1, 2, 3-三氮唑上的N2(产物为2'a~2'f)和N3(产物为2a~2f)原子的亲核性强于N1原子(产物为2a~2f), 因此2a~2f的产率(52%~60%)明显高于2'a~2'f (5%~9%). 2a~2f2'a~2'f的结构表征和文献[26]一致.

    (1)

    2a~2f合成3a~3f的过程是经典的Mannich反应, 本实验选用乙腈作溶剂, 浓盐酸作催化剂, 薄层色谱(TLC)监控反应(以3a为例), 加热回流反应20 min, 首先生成目标产物3a, 反应至50 min时相继生成化合物89, 2 h停止反应, 柱层析分离出化合物89, 经波谱数据分析可知, 8为原料2a和目标产物3a发生迈克尔加成反应的产物, 92a和甲醛发生亲核加成反应的产物.考虑到9在酸性条件下脱水可转化为目标产物3a, 在反应后期补加适量盐酸, 使反应液的pH值始终保持在3~4, 此时9的含量最低, 若酸性继续增加至pH为1~2, 目标产物3a明显减少.

    2'a~2'f转化为3'a~3'f的反应时间较长(8 h), 且没有相应的副产物生成.化合物3a~3f, 3'a~3'f, 89未见文献报道.

    3a~3f3'a~3'f分别与2-氨基苯硫酚在甲醇溶剂中于冰水浴条件下反应1 h, 4a~4f的产率为79%~88%, 4'a~4'f的产率为87%~94%. 4a~4f4'a~4'f在对甲基苯磺酸(PTS)的催化下分子内发生亲核加成-消除反应, 4a~4f生成目标产物3-(1H-1, 2, 3-三氮唑)-4-芳基-2, 5-二氢-1, 5-苯并硫氮杂䓬5a~5f, 4'a~4'f生成目标产物3-(2H-1, 2, 3-三氮唑)-4-芳基-2, 3-二氢-1, 5-苯并硫氮杂䓬6a~6f.对该步反应的催化剂进行了筛选, 醋酸催化原料转化较少, 目标产物收率低; 三氟乙酸催化有副反应发生, 目标产物的分离困难; PTS的催化效果最好, 在甲苯中回流反应25 min, 原料转化趋于完全.氰基硼氢化钠还原5a~5f得到7a~7f, 为了确定7a~7f中七元杂环上两个取代基的相对构型, 培养了化合物7e的单晶, 化合物7e的晶体结构(图 1)显示其为顺式构型.

    图 1

    图 1.  化合物7e的晶体结构
    Figure 1.  Crystal structure of compound 7e

    测试了目标产物5a~5f6a~6f7a~7f对新生隐球菌标准株(C. neoformans stand)、新生隐球菌临床株(C. neoformans clinical)和白色念珠菌(C. albicans)的抑制作用, 抑菌活性数据见表 1.由表 1可知, 化合物5a~5d5f对新生隐球菌(C. neoformans)具有较高的抑制作用, 且对新生隐球菌标准株(C. neoformans stand)和新生隐球菌临床株(C. neoformans clinical)的抑制活性相当, 在200 μg/disc的浓度下, 化合物5a, 5b5f对新生隐球菌(C. neoformans)的抑菌圈直径大于16 mm, 属于该真菌的高度敏感化合物, 尤其是化合物5f (19.44 mm)和对照药物氟康唑(22.40 mm)活性接近, 化合物5c5d对新生隐球菌(C. neoformans)的抑制作用相对于化合物5a, 5b5f虽略有减小, 但仍对该真菌有中度抑制.选择抑真菌活性突出的化合物5a, 5b5f, 进一步测试了其对新生隐球菌(C. neoformans)的最小抑菌浓度(MIC80)和最小杀菌浓度(MFC)(表 2), 由表 2数据可知, 化合物5a, 5b5f的MIC80略高于抗真菌药氟康唑, MFC都低于氟康唑, 因此化合物5a~5f在抗菌药物研究领域具有研究价值.

    表 1

    表 1  化合物5a~5f, 6a~6f7a~7f的抑真菌活性(抑菌圈直径/mm)a, b
    Table 1.  Antifungal activity of compounds 5a~5f, 6a~6f and 7a~7f (diameter of inhibition zone/mm)
    下载: 导出CSV
    Compd. R C. neoformans stand C. neoformans clinical C. albicans
    5a H 16.39 17.08 16.21
    5b F 16.95 16.49 15.56
    5c Cl 12.65 12.29 9.73
    5d Br 12.45 12.23 6.00
    5e CH3 6.00 6.00 6.00
    5f OCH3 19.44 19.19 14.26
    6a H 6.00 6.00 6.00
    6b F 6.00 6.00 6.00
    6c Cl 6.00 6.00 6.00
    6d Br 6.00 6.00 6.00
    6e CH3 6.00 6.00 6.00
    6f OCH3 6.00 6.00 6.00
    7a H 6.00 6.00 6.00
    7b F 6.00 6.00 6.00
    7c Cl 6.00 6.00 6.00
    7d Br 6.00 6.00 6.00
    7e CH3 6.00 6.00 6.00
    7f OCH3 6.00 6.00 6.00
    Fluconazol 22.40 22.40 20.20
    a All values were measured with 200 μg of the tested compound/disk. b The diameter of the filter paper is 6.00 mm, zone of inhibition 6.00 mm considers as no antibacterial activity.

    表 2

    表 2  化合物5a、5b5f对新生隐球菌(C. neoformans)的MIC80和MFC数据(μg/mL)
    Table 2.  MIC80 and MFC values (μg/mL) of compounds 5a, 5b and 5f to C. neoformans
    下载: 导出CSV
    Compd. R MIC80 MFC
    ATCC34874 Clinical isolate ATCC34874 Clinical isolate
    5a H 4.5 4.5 83.0 81.0
    5b F 4.0 4.0 82.0 82.0
    5f OCH3 3.0 3.5 69.0 69.0
    Fluconazol 2.0 3.0 >128.0 >128.0

    根据5a~5f的抑真菌活性, 结合课题组前面的工作, 得出如下的构效关系: 3位不含1H-1, 2, 3-三氮唑取代的相应化合物对新生隐球菌没有抑制作用[28], 说明3位上的1H-1, 2, 3-三氮唑环是5a~5f活性的关键药效基团, 且在相同的位置上, 1H-1, 2, 3-三氮唑比1, 2, 4-三氮唑取代的化合物抑真菌活性有所下降; 4位苯环上的取代基对抑真菌活性有不同程度的影响, 吸电子的卤素按照F, Cl和Br的顺序逐渐下渐, 但取代基提供电子的能力和抑菌活性的关系尚不明确, 有待进一步研究; 值得关注的是当苯环上取代基为甲氧基(5f)时抑真菌效果最好, 具有发展为有效抑真菌物质的前景.为了了解化合物5a~5f中C=C双键结构对抑真菌活性的影响, 还测试了不具有C=C双键的化合物7a~7f对新生隐球菌的抑制作用(表 1), 由表 1数据可知, 化合物7a~7f对待测菌种没有抑制作用.根据药物化学原理, 引起药理活性的前提是活性化合物和受体之间的分子识别和相互作用, 且这种识别和相互作用具有很高的特异性, 因此当活性分子的结构发生改变时, 会引起分子的极性以及空间结构等方面的的变化, 和受体之间的相互作用也随之发生改变, 导致其活性增强、减弱或者消失.从以上的实验结果分析, C=C双键接近于平面的空间构型, 可能是具有活性的主要因素, 7a~7f中双键消失致使活性消失, 这说明C=C双键结构单元是5a~5f抑真菌的必备条件, 这一结果和1, 2, 4-三氮唑取代的相应化合物的抑真菌规律基本一致. 2H-1, 2, 3-三氮唑取代的目标产物6a~6f对待测菌种没有抑制作用.

    设计合成了18个含1, 2, 3-三氮唑取代的1, 5-苯并硫氮杂䓬化合物, 分离出其中两个副产物并进行了结构的鉴定, 7e的单晶结构显示其七元杂环上两个取代基的相对构型为顺式构型; 对目标化合物进行了抑真菌活性测试和构效关系的分析, 发现了对新生隐球菌抑制效果优异的新化合物5a~5f, 初步抑真菌构效关系研究表明, 1H-1, 2, 3-三氮唑环和C=C双键是化合物5a~5f抑真菌活性的关键官能团.该研究结果为含杂环的1, 5-苯并硫氮杂䓬类化合物的深入研究提供了重要参考信息.

    Thermo SCIENTIFIC型红外光谱仪, KBr压片法; 3200QTRAP质谱仪; WIPM-NMR-400M型核磁共振仪TMS为内标; Vario EL Ⅲ型元素分析仪.

    2-氨基苯硫酚购自上海麦克林生化科技有限公司, 其它试剂均为市售分析纯.新生隐球菌标准株(C. neoformans stand)、新生隐球菌临床株(C. neoformans clinical)和白色念珠菌(C. albicans)由河北师范大学生命科学学院提供.

    3.2.1   1-芳基-2-(1H/2H-1, 2, 3-三氮唑)-1-乙酮的合成

    参考文献[26]方法, 在50 mL三口瓶中依次加入1a~1f (2.5 mmol)、10 mL乙腈、0.2 g 1, 2, 3-三氮唑(3 mmol)和0.38 g三乙胺(3.7 mmol), 加热回流反应1 h, 减压浓缩溶剂, 加适量稀盐酸至溶液的pH为5~6, 二氯甲烷萃取反应液, 有机相用无水硫酸钠干燥, 抽滤, 减压浓缩溶剂, 剩余物经硅胶柱层析[V(石油醚):V(乙酸乙酯)=4:1], 分别得到2a~2f2'a~2'f.

    3.2.2   1-芳基-2-(1H/2H-1, 2, 3-三氮唑)-2-丙烯-1-酮合成

    在50 mL三口瓶中依次加入2a~2f (11 mmol)、15 mL乙腈、0.4 g多聚甲醛(14 mmol)、1.3 g二甲胺盐酸盐(16 mmol)和适量盐酸至pH值为3~4, 加热回流反应2 h, 减压浓缩溶剂, 依次加入二氯甲烷和饱和碳酸氢钠水溶液至pH值为7, 分液, 有机相用无水硫酸钠干燥, 浓缩溶剂, 剩余物经硅胶柱层析[V(石油醚):V(乙酸乙酯)=4:1]得到3a~3f, 89. 3'a~3'f的合成步骤同上, 回流反应时间为8 h.

    1-苯基-2-(1H-1, 2, 3-三氮唑)-2-丙烯-1-酮(3a):白色固体, 产率57%. m.p. 106~107 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.06 (s, 1H), 7.86 (d, J=6.4 Hz, 2H), 7.78 (s, 1H), 7.65 (t, J=6.0 Hz, 1H), 7.51 (t, J=6.0 Hz, 2H), 6.78 (s, 1H), 5.98 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 189.8, 139.5, 136.0, 133.9, 133.8, 129.7, 128.7, 124.2, 121.0; ESI-MS m/z: 200.1 (M+H+). Anal. calcd for C11H9N3O: C 66.32, H 4.55, N 21.09; found C 65.92, H 5.00, N 21.31.

    1-(4-氟苯基)-2-(1H-1, 2, 3-三氮唑)-2-丙烯-1-酮(3b):淡黄色固体, 产率54%. m.p. 83~84 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.04 (s, 1H), 7.92 (d, J=8.6 Hz, 2H), 7.78 (s, 1H), 7.20 (t, J=8.6 Hz, 2H), 6.75 (s, 1H), 5.96 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 188.2, 166.7 (d, 1JCF=255.4 Hz), 139.4, 134.0 (d, 3JCF=9.5 Hz), 132.5, 124.0, 120.4, 116.3, 116.0 (d, 2JCF=20.0 Hz); ESI-MS m/z: 218.0 (M+H+). Anal. calcd for C11H8N3OF: C 60.83, H 3.71, N 19.35; found C 60.41, H 3.21, N 19.00.

    1-(4-氯苯基)-2-(1H-1, 2, 3-三氮唑)-2-丙烯-1-酮(3c):黄色油状液体, 产率56%. 1H NMR (CDCl3, 400 MHz) δ: 8.05 (s, 1H), 7.81 (d, J=8.2 Hz, 2H), 7.80 (s, 1H), 7.50 (d, J=8.2 Hz, 2H), 6.77 (s, 1H), 5.97 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 188.6, 140.5, 139.3, 134.0, 133.9, 131.3, 129.3, 129.1, 124.0, 120.8; ESI-MS m/z: 234.2 (M+H+). Anal. calcd for C11H8N3OCl: C 56.55, H 3.45, N 17.98; found C 56.13, H 3.03, N 17.63.

    1-(4-溴苯基)-2-(1H-1, 2, 3-三氮唑)-2-丙烯-1-酮(3d):黄色固体, 产率59%. m.p. 144~145 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.05 (s, 1H), 7.80 (s, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.67 (d, J=8.6 Hz, 2H), 6.78 (s, 1H), 5.97 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 188.8, 134.7, 134.0, 133.1, 132.2, 131.6, 131.1, 129.2, 124.0, 121.0; ESI-MS m/z: 278.1 (M+H+). Anal. calcd for C11H8N3OBr: C 47.51, H 2.90, N 15.11; found C 47.02, H 2.00, N 14.73.

    1-(4-甲基苯基)-2-(1H-1, 2, 3-三氮唑)-2-丙烯-1-酮(3e):黄色油状液体, 产率56%. 1H NMR (CDCl3, 400 MHz) δ: 8.04 (s, 1H), 7.78~7.76 (m, 3H), 7.30 (d, J=7.6 Hz, 2H), 6.72 (s, 1H), 5.94 (s, 1H), 2.44 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 189.4, 145.0, 139.6, 133.9, 133.3, 130.0, 129.4, 124.1, 120.1, 21.7; ESI-MS m/z: 214.1 (M+H+). Anal. calcd for C12H11N3O: C 67.59, H 5.20, N 19.71; found C 67.13, H 5.00, N 19.32.

    1-(4-甲氧基苯基)-2-(1H-1, 2, 3-三氮唑)-2-丙烯-1-酮(3f):黄色油状液体, 产率58%. 1H NMR (CDCl3, 400 MHz) δ: 8.01 (s, 1H), 7.89 (d, J=9.0 Hz, 2H), 7.77 (s, 1H), 6.98 (d, J=9.0 Hz, 2H), 6.68 (s, 1H), 5.89 (s, 1H), 3.90 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 188.2, 164.4, 139.5, 133.9, 132.3, 128.4, 123.9, 118.7, 114.2, 55.6; ESI- MS m/z: 230.1 (M+H+). Anal. calcd for C12H11N3O2: C 62.87, H 4.84, N 18.32; found C 62.45, H 5.05, N 18.54.

    1-苯基-2-(2H-1, 2, 3-三氮唑)-2-丙烯-1-酮(3'a):黄色油状液体, 产率83%. 1H NMR (CDCl3, 400 MHz) δ: 7.83 (d, J=8.4 Hz, 2H), 7.73 (s, 2H), 7.56 (t, J=7.0 Hz, 1H), 7.42 (t, J=7.6 Hz, 2H), 6.34 (s, 1H), 5.64 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 189.0, 143.3, 136.1, 136.0, 135.9, 133.8, 129.5, 128.7, 112.3; ESI-MS m/z: 222.2 (M+Na+). Anal. calcd for C11H9N3O: C 66.32, H 4.55, N 21.09; found C 65.89, H 4.95, N 20.74.

    1-(4-氟苯基)-2-(2H-1, 2, 3-三氮唑)-2-丙烯-1-酮(3'b):黄色油状液体, 产率86%. 1H NMR (CDCl3, 400 MHz) δ: 7.85 (t, J=8.4 Hz, 2H), 7.74 (s, 2H), 7.10 (t, J=8.4 Hz, 2H), 6.33 (s, 1H), 5.64 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 187.5, 166.1 (d, 1JCF=254.9 Hz), 143.0, 136.2, 136.0, 132.2, 116.0 (d, 2JCF=20.2 Hz), 115.7, 112.0, 111.8; ESI-MS m/z: 218.2 (M+H+). Anal. calcd for C11H8N3OF: C 60.83, H 3.71, N 19.35; found C 60.59, H 4.10, N 20.08.

    1-(4-氯苯基)-2-(2H-1, 2, 3-三氮唑)-2-丙烯-1-酮(3'c):黄色油状液体, 产率82%. 1H NMR (CDCl3, 400 MHz) δ: 7.75~7.74 (m, 4H), 7.74 (s, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.34 (s, 1H), 5.66 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 187.8, 143.0, 140.2, 136.2, 136.1, 130.8, 130.7, 129.1, 112.3; ESI-MS m/z: 234.2 (M+H+). Anal. calcd for C11H8N3OCl: C 56.55, H 3.45, N 17.98; found C 56.83, H 4.00, N 17.40.

    1-(4-溴苯基)-2-(2H-1, 2, 3-三氮唑)-2-丙烯-1-酮(3'd):黄色油状液体, 产率81%. 1H NMR (CDCl3, 400 MHz) δ: 7.75 (s, 2H), 7.52 (d, J=8.6 Hz, 2H), 7.57 (d, J=8.6 Hz, 2H), 6.34 (s, 1H), 5.68 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 188.0, 143.0, 136.2, 136.1, 134.6, 132.1, 130.8, 129.1, 112.4; ESI-MS m/z: 278.0 (M+H+). Anal. calcd for C11H8N3OBr: C 47.51, H 2.90, N 15.11; found C 47.98, H 3.45, N 15.36.

    1-(4-甲基苯基)-2-(2H-1, 2, 3-三氮唑)-2-丙烯-1-酮(3'e):黄色油状液体, 产率82%. 1H NMR (CDCl3, 400 MHz) δ: 7.75~7.73 (m, 4H), 7.23 (d, J=8.0 Hz, 2H), 6.31 (s, 1H), 5.61 (s, 1H), 2.40 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 188.7, 144.9, 143.4, 136.0, 135.9, 129.7, 129.6, 129.3, 111.6, 21.8; ESI-MS m/z: 214.2 (M+H+). Anal. calcd for C12H11N3O: C 67.59, H 5.20, N 19.71; found C 67.91, H 5.01, N 20.04.

    1-(4-甲氧基苯基)-2-(2H-1, 2, 3-三氮唑)-2-丙烯-1-酮(3'f):黄色油状液体, 产率80%. 1H NMR (CDCl3, 400 MHz) δ: 7.85 (d, J=8.8 Hz, 2H), 7.75 (s, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.30 (s, 1H), 5.58 (s, 1H), 3.87 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 187.7, 164.2, 143.3, 136.0, 135.9, 132.1, 128.7, 114.0, 110.8, 65.5; ESI-MS m/z: 230.1 (M+H+). Anal. calcd for C12H11N3O2: C 62.87, H 4.84, N 18.32; found C 62.59, H 5.00, N 18.69.

    1, 5-二苯基-2, 4-二-(1H-1, 2, 3-三氮唑)-1, 5-戊二酮(8):无色油状液体, 产率15%. 1H NMR (CDCl3, 400 MHz) δ: 8.04 (s, 1H), 8.02 (s, 1H), 7.88~7.86 (m, 3H), 7.82~7.61 (m, 8H), 7.54~7.47 (m, 6H), 6.28 (t, J=6.5 Hz, 1H), 6.13 (dd, J=6.5, 1.5H), 3.48~3.42 (m, 0.5H), 3.24 (t, J=6.5 Hz, 1.5H), 2.70~2.64 (m, 0.5H); 13C NMR (CDCl3, 100 MHz) δ: 192.0, 134.8, 133.2, 129.2, 128.7, 124.4, 122.9, 60.6, 29.7; ESI-MS m/z: 387.8 (M+H+). Anal. calcd for C21H18N6O2: C 65.28, H 4.66, N 21.76; found C 64.93, H 5.00, N 21.31.

    1-苯基-2-(1H-1, 2, 3-三氮唑)-3-羟基-1-丙酮(9):无色油状液体, 产率10%. 1H NMR (CDCl3, 400 MHz) δ: 7.98 (d, J=6.0 Hz, 2H), 7.85 (s, 1H), 7.71 (s, 1H), 7.63 (t, J=6.0 Hz, 1H), 7.49 (t, J=6.0 Hz, 2H), 6.47 (t, J=4.2, 3.6 Hz, 1H), 4.38 (dd, J=4.2, 9.6 Hz, 1H), 4.32 (dd, J=3.6, 9.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 193.0, 134.6, 134.1, 129.2, 128.8, 124.2, 65.3, 62.9; ESI-MS m/z: 218.2 (M+H+). Anal. calcd for C11H11N3O2: C 60.83, H 5.07, N 19.35; found C 60.40, H 5.49, N 18.94.

    3.2.3   1-芳基-2-(1H/2H-1, 2, 3-三氮唑)-3-(2-氨基苯硫基)-1-丙酮的合成

    在50 mL三口瓶中依次加入3a~3f (3.5 mmol)、0.44 g 2-氨基苯硫酚(3.5 mmol)和10 mL无水甲醇, 冰水浴下反应1 h, 减压浓缩溶剂, 剩余物冷冻析出固体, 乙醚重结晶得到化合物4a~4f.按照相同的步骤得到化合物4'a~4'f.

    1-苯基-2-(1H-1, 2, 3-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(4a):无色油状液体, 产率82%. 1H NMR (CDCl3, 400 MHz) δ: 7.79 (s, 1H), 7.76~7.73 (m, 3H), 7.58 (t, J=6.0 Hz, 1H), 7.41~7.36 (m, 2H), 7.40 (s, 1H), 7.21 (t, J=6.0 Hz, 1H), 6.77 (d, J=6.0 Hz, 1H), 6.73 (t, J=6.0 Hz, 1H), 6.45 (dd, J=7.6, 4.0 Hz, 1H), 4.36 (s, 2H), 3.60 (dd, J=7.6, 11.6 Hz, 1H), 3.28 (dd, J=4.0, 11.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 192.4, 149.1, 137.2, 134.5, 134.3, 133.7, 131.1, 129.1, 128.9, 123.1, 118.9, 115.3, 114.7, 62.6, 37.0; ESI-MS m/z: 347.1 (M+Na+). Anal. calcd for C17H16N4OS: C 62.96, H 4.94, N 17.28; found C 62.54, H 4.27, N 17.51.

    1-(4-氟苯基)-2-(1H-1, 2, 3-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(4b):淡黄色油状液体, 产率85%. 1H NMR (CDCl3, 400 MHz) δ: 7.83~7.78 (m, 4H), 7.40 (d, J=7.6 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.10 (t, J=8.4 Hz, 2H), 6.82 (d, J=8.0 Hz, 1H), 6.77 (t, J=7.6 Hz, 1H), 6.45~6.41 (m, 1H), 4.44 (s, 2H), 3.62 (dd, J=5.2, 14.4 Hz, 1H), 3.31 (dd, J=14.4, 9.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 190.9, 166.4 (d, 1JCF=256.7 Hz), 149.0, 137.2, 134.4, 131.8 (d, 3JCF=8.0 Hz), 131.2, 130.2, 123.0, 119.0, 116.4 (d, 2JC=21.7 Hz), 115.4, 114.6, 62.4, 36.8; ESI-MS m/z: 343.2 (M+H+). Anal. calcd for C17H15N4OFS: C 59.64, H 4.42, N 16.36; found C 60.03, H 4.16, N 16.52.

    1-(4-氯苯基)-2-(1H-1, 2, 3-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(4c):淡黄色油状液体, 产率88%. 1H NMR (CDCl3, 400 MHz) δ: 7.85 (s, 1H), 7.72 (s, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.16 (t, J=7.2 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.66 (t, J=7.2 Hz, 1H), 6.37~6.34 (m, 1H), 4.53 (s, 2H), 3.56 (dd, J=4.0, 14.4 Hz, 1H), 3.28 (dd, J=14.4, 9.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 191.2, 149.2, 140.9, 137.1, 134.3, 131.9, 131.2, 130.2, 129.3, 123.7, 118.7, 115.4, 114.3, 62.8, 36.4; ESI-MS m/z: 359.1 (M+H+). Anal. calcd for C17H15N4OClS: C 56.90, H 4.21, N 15.61; found C 56.57, H 4.49, N 15.99.

    1-(4-溴苯基)-2-(1H-1, 2, 3-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(4d):淡黄色油状液体, 产率79%. 1H NMR (CDCl3, 400 MHz) δ: 7.79 (s, 1H), 7.74 (s, 1H), 7.57~7.49 (m, 4H), 7.35 (d, J=7.6 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 6.72 (t, J=7.6 Hz, 1H), 6.37~6.34 (m, 1H), 4.43 (s, 2H), 3.57 (dd, J=4.4, 14.4 Hz, 1H), 3.26 (dd, J=14.4, 9.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 191.5, 149.1, 137.2, 134.4, 132.4, 131.2, 130.3, 130.2, 130.0, 123.1, 119.0, 115.5, 115.3, 114.5, 62.5, 36.6; ESI-MS m/z: 403.0 (M+H+). Anal. calcd for C17H15N4OSBr: C 50.63, H 3.75, N 13.89; found C 50.40, H 3.94, N 13.47.

    1-(4-甲基苯基)-2-(1H-1, 2, 3-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(4e):淡黄色油状液体, 产率87%. 1H NMR (CDCl3, 400 MHz) δ: 7.82 (s, 1H), 7.71 (s, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.34 (d, J=7.2 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 2H), 6.76 (d, J=8.0 Hz, 1H), 6.69 (t, J=7.2 Hz, 1H), 6.42~6.39 (m, 1H), 4.48 (s, 2H), 3.57 (dd, J=4.8, 14.4 Hz, 1H), 3.25 (dd, J=14.4, 10.0 Hz, 1H), 2.32 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 191.9, 149.2, 145.7, 137.1, 134.2, 131.1, 129.8, 129.0, 123.4, 118.7, 115.4, 114.6, 62.6, 36.9, 21.7; ESI-MS m/z: 339.2 (M+H+). Anal. calcd forC18H18N4OS: C 63.88, H 5.36, N 16.56; found C 64.04, H 5.27, N 16.84.

    1-(4-甲氧基苯基)-2-(1H-1, 2, 3-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(4f):淡黄色油状液体, 产率84%. 1H NMR (CDCl3, 400 MHz) δ: 7.81 (s, 1H), 7.72~7.71 (m, 3H), 7.36 (d, J=7.6 Hz, 1H), 7.20 (t, J=8.8 Hz, 1H), 6.83 (d, J=8.0 Hz, 2H), 6.77 (d, J=7.6 Hz, 1H), 6.71 (t, J=7.2 Hz, 1H), 6.41~6.37 (m, 1H), 4.44 (s, 2H), 3.57 (dd, J=4.8, 14.4 Hz, 1H), 3.26 (dd, J=14.4, 9.6 Hz, 1H), 3.82 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 190.7, 164.6, 149.1, 137.1, 134.2, 131.4, 131.3, 131.0, 126.6, 123.1, 118.8, 115.4, 114.8, 114.4, 114.2, 62.2, 55.6, 37.1; ESI-MS m/z: 355.1 (M+H+). Anal. calcd for C18H18N4O2S: C 61.00, H 5.12, N 15.81; found C 61.38, H 5.34, N 15.30.

    1-苯基-2-(2H-1, 2, 3-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(4'a):白色固体, 产率94%. m.p. 100~101 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.70~6.83 (m, 4H), 7.52 (t, J=7.4 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.34 (t, J=7.8 Hz, 2H), 7.22 (t, J=7.4 Hz, 1H), 6.80~6.73 (m, 2H), 6.22 (t, J=7.2 Hz, 1H), 4.43 (s, 2H), 3.66 (d, J=7.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 192.0, 149.1, 137.4, 135.2, 134.3, 133.9, 128.8, 118.8, 115.4, 115.2, 67.4, 35.7; ESI-MS m/z: 347.1 (M+Na+). Anal. calcd for C17H16N4- OS: C 62.96, H 4.94, N 17.28; found C 62.53, H 4.86, N 16.89.

    1-(4-氟苯基)-2-(2H-1, 2, 3-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(4'b):淡黄色固体, 产率88%. m.p. 82~83 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.73~7.70 (m, 2H), 7.67 (s, 2H), 7.41 (d, J=7.2 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.98 (t, J=8.0 Hz, 2H), 6.74 (d, J=10.4 Hz, 1H), 6.69 (t, J=6.4 Hz, 1H), 6.16 (t, J=7.0 Hz, 1H), 4.44 (s, 2H), 3.64 (d, J=6.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 190.5, 166.0 (d, 1JCF=255.3 Hz), 149.1, 135.3, 131.6 (d, 3JCF=8.5 Hz), 131.0, 130.7, 118.2, 116.1 (d, 2JCF=21.1 Hz), 115.2, 67.3, 35.5; ESI-MS m/z: 343.2 (M+H+). Anal. calcd for C17H15N4OFS: C 59.64, H 4.42, N 16.36; found C 60.00, H 4.87, N 16.82.

    1-(4-氯苯基)-2-(2H-1, 2, 3-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(4'c):淡黄色固体, 产率90%. m.p. 86~87 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.67 (s, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.40 (d, J=7.6 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.19 (t, J=7.6 Hz, 1H), 6.77~6.72 (m, 2H), 6.15 (t, J=6.8 Hz, 1H), 4.45 (s, 2H), 3.63 (d, J=6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 190.9, 149.1, 140.4, 135.3, 135.2, 132.6, 130.1, 129.1, 118.8, 115.3, 115.2, 67.3, 35.5; ESI-MS m/z: 359.2 (M+H+). Anal. calcd for C17H15N4OClS: C 56.90, H 4.21, N 15.61; found C 56.47, H 4.37, N 16.01.

    1-(4-溴苯基)-2-(2H-1, 2, 3-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(4'd):淡黄色油状液体, 产率91%. 1H NMR (CDCl3, 400 MHz) δ: 7.66 (s, 2H), 7.53~7.42 (m, 4H), 7.18 (t, J=8.8 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.74~6.65 (m, 2H), 6.13 (t, J=7.2 Hz, 1H), 4.42 (s, 2H), 3.62 (d, J=7.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 191.1, 149.1, 135.4, 135.2, 133.0, 132.1, 131.0, 130.2, 130.1, 129.3, 118.8, 118.1, 115.3, 115.2, 67.1, 35.5; ESI-MS m/z: 403.0 (M+H+). Anal. calcd for C17H15N4OSBr: C 50.63, H 3.75, N 13.89; found C 50.98, H 3.94, N 14.02.

    1-(4-甲基苯基)-2-(2H-1, 2, 3-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(4'e):淡黄色固体, 产率88%. m.p. 94~95 ℃. 1H NMR (CDCl3, 400 MHz) δ: 7.67 (s, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.41 (d, J=7.6 Hz, 1H), 7.19 (t, J=6.8 Hz, 1H), 7.11 (d, J=8.0 Hz, 2H), 6.76 (d, J=7.6 Hz, 1H), 6.72 (t, J=7.6 Hz, 1H), 6.20 (t, J=6.0 Hz, 1H), 4.44 (s, 2H), 3.85 (d, J=6.0 Hz, 2H), 2.32 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 191.6, 149.2, 145.0, 137.3, 135.1, 131.7, 130.9, 129.5, 128.9, 118.7, 115.4, 115.2, 67.3, 35.7, 21.7; ESI-MS m/z: 339.1 (M+H+). Anal. calcd for C18H18N4OS: C 63.88, H 5.36, N 16.56; found C 63.53, H 5.29, N 16.89.

    1-(4-甲氧基苯基)-2-(2H-1, 2, 3-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(4'f):淡黄色油状液体, 产率87%. 1H NMR (CDCl3, 400 MHz) δ: 7.71~7.68 (m, 4H), 7.42 (d, J=7.6 Hz, 1H), 7.20 (t, J=7.2 Hz, 1H), 6.82~6.72 (m, 4H), 6.18 (dd, J=8.8, 5.2 Hz, 1H), 4.44 (s, 2H), 3.82 (s, 3H), 3.67 (dd, J=8.8, 14.0 Hz, 1H), 3.63 (dd, J=14.0, 5.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 190.3, 164.1, 149.1, 135.1, 134.9, 131.2, 131.1, 127.2, 118.8, 118.6, 115.5, 115.3, 115.1, 114.1, 113.9, 67.1, 55.4, 35.8; ESI-MS m/z: 355.2 (M+H+). Anal. calcd for C18H18N4O2S: C 61.00, H 5.12, N 15.81; found C 60.59, H 5.42, N 16.12.

    3.2.4   3-(1H-1, 2, 3-三氮唑)-4-芳基-2, 5-二氢-1, 5-苯并硫氮杂䓬的合成

    在50 mL三口瓶中加入4a~4f (6.2 mmol)、15 mL甲苯和适量对甲基苯磺酸(PTS), 加热回流分水25 min, 将反应液冷却至室温, 减压浓缩溶剂, 加入适量乙醇, 冷冻析出固体, 乙醇重结晶得到5a~5f.

    3-(1H-1, 2, 3-三氮唑)-4-苯基-2, 5-二氢-1, 5-苯并硫氮杂䓬(5a):白色固体, 产率43%. m.p. 182~184 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.42 (d, J=6.0 Hz, 1H), 7.34 (s, 1H), 7.29~7.24 (m, 5H), 7.20 (t, J=6.0 Hz, 1H), 7.04 (s, 1H), 6.95 (t, J=6.0 Hz, 1H), 6.89 (d, J=6.4 Hz, 1H), 6.07 (s, 1H), 3.94 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 143.6, 139.8, 136.9, 133.7, 132.8, 129.4, 128.9, 128.3, 126.2, 125.8, 121.9, 121.2, 114.0, 38.1; IR (KBr) ν: 3161, 1664 cm-1; ESI-MS m/z: 307.2 (M+H+). Anal. calcd for C17H14N4S: C 66.64, H 4.61, N 18.29; found C 66.23, H 4.27, N 18.64.

    3-(1H-1, 2, 3-三氮唑)-4-(4-氟苯基)-2, 5-二氢-1, 5-苯并硫氮杂䓬(5b):白色固体, 产率37%. m.p. 156~158 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.42 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 7.27~7.19 (m, 3H), 7.07 (s, 1H), 6.96~6.89 (m, 4H), 6.04 (s, 1H), 3.92 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 163.0 (d, 1JCF=249.0 Hz), 143.5, 139.0, 133.7, 132.9, 130.3 (d, 3JCF=8.3 Hz), 128.4, 126.0, 125.8, 122.1, 121.2, 116.0 (d, 2JCF=21.6 Hz), 114.1, 38.1; IR (KBr) ν: 3131, 1660 cm-1; ESI-MS m/z: 325.2 (M+ H+). Anal. calcd for C17H13N4FS: C 62.95, H 4.04, N 17.27; found C 62.53, H 3.65, N 17.76.

    3-(1H-1, 2, 3-三氮唑)-4-(4-氯苯基)-2, 5-二氢-1, 5-苯并硫氮杂䓬(5c):白色固体, 产率41%. m.p. 190~191 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.50 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.27~7.19 (m, 5H), 7.08 (s, 1H), 6.97 (t, J=7.6 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.04 (s, 1H), 3.92 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 143.4, 138.9, 135.3, 133.8, 133.1, 130.4, 129.7, 129.2, 128.8, 128.4, 126.4, 126.1, 124.0, 122.2, 121.2, 114.3, 38.2; IR (KBr) ν: 3051, 1647 cm-1; ESI-MS m/z: 341.2 (M+H+). Anal. calcd for C17H13N4SCl: C 59.91, H 3.84, N 16.44; found C 59.52, H 3.46, N 16.92.

    3-(1H-1, 2, 3-三氮唑)-4-(4-溴苯基)-2, 5-二氢-1, 5-苯并硫氮杂䓬(5d):白色固体, 产率40%. m.p. 188~189 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.43~7.38 (m, 4H), 7.22 (t, J=7.2 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.08 (s, 1H), 6.97 (t, J=7.2 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 5.97 (s, 1H), 3.92 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 143.4, 138.9, 135.8, 133.8, 133.1, 132.1, 129.9, 128.4, 126.1, 125.9, 123.8, 122.2, 121.2, 114.3, 38.2; IR (KBr) ν: 3082, 1665 cm-1; ESI-MS m/z: 385.1 (M+H+). Anal. calcd for C17H13N4SBr: C 53.00, H 3.40, N 14.54; found C 52.64, H 3.62, N 14.87.

    3-(1H-1, 2, 3-三氮唑)-4-(4-甲基苯基)-2, 5-二氢-1, 5-苯并硫氮杂䓬(5e):白色固体, 产率38%. m.p. 180~182 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.41 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 7.19 (t, J=7.6 Hz, 1H), 7.13 (d, J=8.0 Hz, 2H), 7.05~7.04 (m, 3H), 6.94 (t, J=7.2 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.09 (s, 1H), 3.98 (s, 2H), 2.34 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 143.5, 139.7, 139.6, 134.0, 133.6, 132.8, 129.6, 128.2, 128.1, 126.2, 125.7, 121.8, 121.1, 114.0, 38.1, 21.3; IR (KBr) ν: 3140, 1650 cm-1; ESI-MS m/z: 321.1 (M+H+). Anal. calcd for C18H16N4S: C 67.47, H 5.03, N 17.49; found C 67.03, H 5.21, N 17.74.

    3-(1H-1, 2, 3-三氮唑)-4-(4-甲氧基苯基)-2, 5-二氢- 1, 5-苯并硫氮杂䓬(5f):白色固体, 产率38%. m.p. 158~159 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.41~7.31 (m, 2H), 7.17 (d, J=7.6 Hz, 3H), 7.06 (s, 1H), 6.93 (t, J=7.2 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 2H), 6.04 (s, 1H), 3.94 (s, 2H), 3.76 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 160.2, 143.4, 139.4, 133.6, 132.9, 129.6, 129.0, 128.2, 126.2, 125.6, 121.7, 121.1, 114.2, 55.3, 38.0; IR (KBr) ν: 3148, 1641 cm-1; ESI-MS m/z: 337.1 (M+ H+). Anal. calcd for C18H16N4OS: C 64.27, H 4.79, N 16.65; found C 63.87, H 4.38, N 16.90.

    3.2.5   3-(2H-1, 2, 3-三氮唑)-4-芳基-2, 3-二氢-1, 5苯并硫氮杂䓬的合成

    6a~6f的合成步骤同5a~5f.

    3-(2H-1, 2, 3-三氮唑)-4-苯基-2, 3-二氢-1, 5-苯并硫氮杂䓬(6a):黄色固体, 产率82%. m.p. 136~137 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.64 (d, J=7.6 Hz, 1H), 7.53 (d, J=7.2 Hz, 2H), 7.47 (s, 2H), 7.45 (d, J8.0 Hz, 1H), 7.33 (t, J=8.0 Hz, 2H), 7.26 (t, J=8.0 Hz, 2H), 7.14 (t, J=7.6 Hz, 1H), 5.78 (dd, J=6.6, 6.6 Hz, 1H), 4.53 (t, J=12.2 Hz, 1H), 4.35 (dd, J=12.2, 6.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 168.5, 151.0, 136.5, 134.6, 130.2, 128.2, 127.2, 125.8, 125.1, 122.4, 64.3, 43.4; IR (KBr) ν: 1617 cm-1; ESI-MS m/z: 307.2 (M+H+). Anal. calcd for C17H14N4S: C 66.64, H 4.61, N 18.29; found C 66.25, H 4.74, N 18.56.

    3-(2H-1, 2, 3-三氮唑)-4-(4-氟苯基)-2, 3-二氢-1, 5-苯并硫氮杂䓬(6b):黄色固体, 产率80%. m.p. 150~151 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.64 (d, J=7.2 Hz, 1H), 7.55~7.45 (m, 5H), 7.34 (d, J=8.0 Hz, 1H), 7.13 (t, J=7.6 Hz, 1H), 6.95 (t, J=8.4 Hz, 2H), 5.77 (dd, J=6.6, 6.4 Hz, 1H), 4.48 (t, J=12.2 Hz, 1H), 4.35 (dd, J=12.2, 6.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 167.2, 163.9 (d, 1JCF=249.3 Hz), 150.8, 134.7, 134.6, 130.3, 129.5 (d, 3JCF=8.6 Hz), 125.9, 125.1, 122.4, 115.3 (d, 2JCF=21.7 Hz), 64.2, 43.3; IR (KBr) ν: 1602 cm-1; ESI-MS m/z: 325.1 (M+H+). Anal. calcd for C17H13N4FS: C 62.95, H 4.04, N 17.27; found C 62.56, H 3.73, N 17.67.

    3-(2H-1, 2, 3-三氮唑)-4-(4-氯苯基)-2, 3-二氢-1, 5-苯并硫氮杂䓬(6c):黄色固体, 产率83%. m.p. 162~163 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.64 (d, J=7.6 Hz, 1H), 7.50~7.45 (m, 5H), 7.34 (d, J=8.0 Hz, 1H), 7.24 (t, J=8.4 Hz, 2H), 7.14 (t, J=7.2 Hz, 1H), 5.76 (dd, J=6.6, 6.4 Hz, 1H), 4.48 (t, J=12.2 Hz, 1H), 4.35 (dd, J=12.2, 6.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 167.2, 150.7, 136.4, 134.9, 134.7, 134.6, 130.3, 128.7, 128.4, 126.0, 125.2, 122.4, 64.2, 43.4; IR (KBr) ν: 1615 cm-1; ESI-MS m/z: 341.1 (M+H+). Anal. calcd for C17H13N4SCl: C 59.91, H 3.84, N 16.44; found C 59.58, H 3.54, N 16.74.

    3-(2H-1, 2, 3-三氮唑)-4-(4-溴苯基)-2, 3-二氢-1, 5-苯并硫氮杂䓬(6d):黄色固体, 产率85%. m.p. 165~166 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.64 (d, J=7.6 Hz, 1H), 7.50 (s, 2H), 7.47 (t, J=7.6 Hz, 1H), 7.40 (t, J=8.8 Hz, 4H), 7.34 (d, J=8.0 Hz, 1H), 7.14 (t, J=7.6 Hz, 1H), 5.76 (dd, J=6.6, 6.4 Hz, 1H), 4.47 (t, J=12.2 Hz, 1H), 4.35 (dd, J=12.2, 6.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 167.3, 150.7, 134.7, 134.6, 131.3, 130.3, 128.9, 126.0, 125.2, 122.4, 64.1, 43.4; IR (KBr) ν: 1611 cm-1; ESI-MS m/z: 385.1 (M+H+). Anal. calcd for C17H13N4SBr: C 53.00, H 3.40, N 14.54; found C 52.53, H 3.62, N 14.84.

    3-(2H-1, 2, 3-三氮唑)-4-(4-甲基苯基)-2, 3-二氢-1, 5-苯并硫氮杂䓬(6e):黄色固体, 产率82%. m.p. 148~150 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.62 (d, J=7.6 Hz, 1H), 7.49 (s, 2H), 7.44 (t, J=8.0 Hz, 3H), 7.33 (d, J=7.2 Hz, 1H), 7.12~7.05 (m, 3H), 5.77 (dd, J=6.6, 6.4 Hz, 1H), 4.51 (t, J=12.0 Hz, 1H), 4.34 (dd, J=12.0, 6.4 Hz, 1H), 2.30 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 168.1, 151.1, 140.6, 134.5, 133.6, 130.2, 128.9, 127.2, 125.6, 125.1, 122.4, 64.2, 43.3, 21.4; IR (KBr) ν: 1615 cm-1; ESI-MS m/z: 321.1 (M+H+). Anal. calcd for C18H16N4S: C 67.47, H 5.03, N 17.49; found C 67.05, H 4.74, N 17.79.

    3-(2H-1, 2, 3-三氮唑)-4-(4-甲氧基苯基)-2, 3-二氢- 1, 5-苯并硫氮杂䓬(6f):黄色固体, 产率79%. m.p. 122~124 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.61 (d, J=7.6 Hz, 1H), 7.53~7.50 (d, J=9.2 Hz, 4H), 7.43 (t, J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H), 6.77 (d, J=8.8 Hz, 2H), 5.77 (dd, J=6.4, 6.4 Hz, 1H), 4.49 (t, J=12.0 Hz, 1H), 4.35 (dd, J=12.0, 6.4 Hz, 1H), 3.77 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 167.3, 161.3, 151.2, 134.5, 130.2, 129.0, 128.9, 125.5, 125.0, 122.3, 113.6, 64.1, 55.3, 43.2; IR (KBr) ν: 1602 cm-1; ESI-MS m/z: 337.2 (M+H+). Anal. calcd for C18H16N4OS: C 64.27, H 4.79, N 16.65; found C 63.88, H 4.32, N 16.85.

    3.2.6   3-(1H-1, 2, 3-三氮唑)-4-芳基-2, 3, 4, 5-四氢-1, 5-苯并硫氮杂䓬的合成

    在50 mL三口瓶中, 分别加入5a~5f (0.33 mmol)、20.6 mg氰基硼氢化钠(0.33 mmol)、适量溴甲酚绿、5 mL四氢呋喃和5 mL甲醇, 于冰水浴条件下滴加乙酸和甲醇(体积比为1:1)混合液, 当反应液颜色变为黄色时停止滴加, 继续搅拌1 h, 减压浓缩溶剂, 加入乙酸乙酯和饱和碳酸氢钠溶液调节pH为10, 分液, 有机相浓缩, 加入适量乙醚和石油醚, 析出固体, 乙醚重结晶得到7a~7f.

    3-(1H-1, 2, 3-三氮唑)-4-苯基-2, 3, 4, 5-四氢-1, 5-苯并硫氮杂䓬(7a):白色固体, 产率83%. m.p. 182~184 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.29 (s, 1H), 7.63 (s, 1H), 7.36~6.71 (m, 9H), 5.38 (s, 1H), 5.32 (dd, J=8.2, 4.6 Hz, 1H), 3.86 (s, 1H), 3.82 (dd, J=14.6, 8.2 Hz, 1H), 3.30 (dd, J=14.6, 4.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 148.6, 138.8, 133.1, 132.1, 129.0, 128.5, 128.1, 125.8, 124.4, 121.7, 120.5, 64.1, 63.1, 35.8; IR (KBr) ν: 3331 cm-1; ESI-MS m/z: 331.1 (M+Na+). Anal. calcd for C17H16N4S: C 66.21, H 5.23, N 18.17; found C 65.87, H 4.85, N 17.82.

    3-(1H-1, 2, 3-三氮唑)-4-(4-氟苯基)-2, 3, 4, 5-四氢-1, 5-苯并硫氮杂䓬(7b):白色固体, 产率81%. m.p. 158~160 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.30 (s, 1H), 7.65 (s, 1H), 7.34~6.71 (m, 8H), 5.37 (s, 1H), 5.28 (dd, J=8.0, 4.6 Hz, 1H), 3.81 (dd, J=14.6, 8.0 Hz, 1H), 3.76 (s, 1H), 3.30 (dd, J=14.6, 4.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 162.4 (d, 1JCF=246.7 Hz), 148.4, 134.7, 133.2, 132.2, 128.1, 127.6 (d, 3JCF=8.1 Hz), 124.4, 121.8, 120.5, 116.0 (d, 2JCF=21.4 Hz), 64.0, 62.4, 35.7; IR (KBr) ν: 3351 cm-1; ESI-MS m/z: 349.1 (M+Na+). Anal. calcd for C17H15N4FS: C 62.56, H 4.63, N 17.17; found C 62.17, H 4.27, N 16.85.

    3-(1H-1, 2, 3-三氮唑)-4-(4-氯苯基)-2, 3, 4, 5-四氢-1, 5-苯并硫氮杂䓬(7c):白色固体, 产率82%. m.p. 163~165 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.29 (s, 1H), 7.65 (s, 1H), 7.36~6.71 (m, 8H), 5.37 (s, 1H), 5.29 (dd, J=8.4, 4.8 Hz, 1H), 3.82 (dd, J=14.8, 8.4 Hz, 1H), 3.77 (s, 1H), 3.30 (dd, J=14.8, 4.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 148.3, 137.3, 134.4, 133.2, 132.2, 129.2, 128.1, 127.2, 124.4, 121.9, 120.5, 63.9, 62.5, 35.7; IR (KBr) ν: 3337 cm-1; ESI-MS m/z: 365.2 (M+Na+). Anal. calcd for C17H15N4SCl: C 59.56, H 4.41, N 16.34; found C 59.21, H 4.03, N 16.01.

    3-(1H-1, 2, 3-三氮唑)-4-(4-溴苯基)-2, 3, 4, 5-四氢-1, 5-苯并硫氮杂䓬(7d):白色固体, 产率84%. m.p. 118~120 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.31 (s, 1H), 7.66 (s, 1H), 7.36~6.70 (m, 8H), 5.35 (s, 1H), 5.30 (dd, J=8.0, 4.8 Hz, 1H), 3.81 (dd, J=14.4, 8.0 Hz, 1H), 3.77 (s, 1H), 3.31 (dd, J=14.4, 4.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 148.3, 137.7, 133.2, 132.2, 128.1, 127.5, 124.4, 122.6, 122.5, 121.9, 120.6, 63.9, 62.5, 35.7; IR (KBr) ν: 3357 cm-1; ESI-MS m/z: 409.1 (M+Na+). Anal. calcd for C17H15N4SBr: C 52.72, H 3.90, N 14.47; found C 52.34, H 3.49, N 14.13.

    3-(1H-1, 2, 3-三氮唑)-4-(4-甲基苯基)-2, 3, 4, 5-四氢- 1, 5-苯并硫氮杂䓬(7e):白色固体, 产率81%. m.p. 155~156 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.33 (s, 1H), 7.65 (s, 1H), 7.36~6.70 (m, 8H), 5.32 (s, 1H), 5.30 (dd, J=8.0, 4.6 Hz, 1H), 3.81 (s, 1H), 3.79 (dd, J=14.6, 8.0 Hz, 1H), 3.30 (dd, J=14.6, 4.6 Hz, 1H), 2.26 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 148.7, 138.3, 135.9, 133.1, 132.1, 129.7, 128.0, 125.6, 124.4, 121.6, 120.4, 64.1, 62.8, 35.8, 21.1; IR (KBr) ν: 3357 cm-1. ESI-MS m/z: 345.2 (M+ Na+). Anal. calcd for C18H18N4S: C 67.05, H 5.63, N 17.38; found C 66.71, H 5.25, N 17.02.

    3-(1H-1, 2, 3-三氮唑)-4-(4-甲氧基苯基)-2, 3, 4, 5-四氢- 1, 5-苯并硫氮杂䓬(7f):白色固体, 产率78%. m.p. 126~128 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.31 (s, 1H), 7.65 (s, 1H), 7.35~6.69 (m, 8H), 5.31 (s, 1H), 5.27 (dd, J=8.4, 4.6 Hz, 1H), 3.78 (s, 1H), 3.76 (dd, J=14.6, 8.4 Hz, 1H), 3.72 (s, 3H), 3.28 (dd, J=14.6, 4.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 159.4, 148.7, 133.1, 132.1, 131.0, 128.0, 127.0, 124.5, 121.6, 120.4, 114.3, 64.2, 62.5, 55.2, 35.8; IR (KBr) ν: 3354 cm-1; ESI-MS m/z: 361.1 (M+ Na+). Anal. calcd for C18H18N4OS: C 63.88, H 5.36, N 16.56; found C 63.64, H 5.09, N 16.31.

    3.2.7   7e晶体结构的测定

    7e溶于少量甲醇中, 室温下缓慢挥发, 得到7e的单晶. 7e的晶体数据存于剑桥晶体数据库, 其CCDC号为1954727.选取0.40 mm×0.32 mm×0.20 mm大小的单晶, 在298 K的温度下, 在SMART APEXⅡCCD Area Detector衍射仪上采用Mo Kα射线(λ=0.071073 nm)在2.57°≤θ≤25.02°范围内以φ-ω方式进行扫描, 共收集了15178个衍射点, 其中独立衍射点为2879个[R(int)]=0.0470.晶体结构属正交晶系(Orthorhombic), 晶胞参数为a=0.94896(9) nm, b=1.19676(11) nm, c=2.8711(3) nm, α=90°, β=90°, γ=90°, V=3.2607(5) nm3, Dc=1.314 Mg•m-3, Z=8, F(000)=1360. Pbca空间群, μ=0.203 mm-1.

    采用酵母滤纸法[29]对目标产物的抑菌活性进行了测定, 以氟康唑作为抑真菌的对照药物, 以抑菌圈直径(单位: mm)的大小表示物质抑菌活性的大小, 测定其对新生隐球菌标准株(C. neoformans stand)、新生隐球菌临床株(C. neoformans clinical)和白色念珠菌(C. albicans)的抑制作用.

    将化合物5a~5f, 6a~6f7a~7f用二甲基亚砜(DMSO)配成溶液, 用微量进样器加到滤纸片上, 使每片含药量为200 μg, 置于室温使DMSO挥发后备用.将对数生长期的菌种用Meller-Hinton (MH)液体培养基稀释成106个/mL CFU, 均取0.2 mL加到MH琼脂平板上, 将含药滤纸片贴于培养基上, 于孵化箱内37 ℃培养24 h, 记录实验结果, 实验重复三次, 抑菌结果取其平均值.

    辅助材料(Supporting Information)中间体3a~3f3'a~3'f4a~4f4'a~4'f及目标化合物5a~5f6a~6f7a~7f1H 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.


    1. [1]

      Balaban, A. T.; Oniciu, D. C.; Katritzky, A. R. Chem. Rev. 2004, 104, 2777. doi: 10.1021/cr0306790

    2. [2]

      赵雁来, 何森泉, 徐长德, 杂环化学导论, 高等教育出版社, 北京, 1992, p. 13.Zhao, Y. L.; He, S. Q.; Xu, C. D. Introduction to Heterocyclic Chemistry, Higher Education Press, Beijing, 1992, p. 13(in Chinese).

    3. [3]

      Giller, S. A.; Zaeva, S. P.; Venter, K. K.; Alekseeva, L. N.; Kruzmetra, L. V.; Germane, S. K. Chem. Heterocycl. Compd. 1965, 1, 122. 

    4. [4]

      Liao, Y.; Bastiaan, J. V.; Nienke, R.; Wia, T.; Hakan, W. J. Med. Chem. 1999, 42, 2235. doi: 10.1021/jm991005d

    5. [5]

      许同绣, 王岩, 田克情, 王冉冉, 闫静怡, 张萍, 有机化学, 2018, 38, 2731.Xu, T. X.; Wang, Y.; Tian, K. Q.; Wang, R. R.; Yan, J. Y.; Zhang, P. Chin. J. Org. Chem. 2018, 38, 2731(in Chinese). 

    6. [6]

      Sarro, G. D.; Chimirri, A.; Sarro, A. D.; Gitto, R.; Grasso, S.; Zappala, M. Eur. J. Med. Chem. 1995, 30, 925. doi: 10.1016/0223-5234(96)88311-5

    7. [7]

      Karnail, S. A.; James, L. B.; Anders, H.; Suzanne, M. J. Med. Chem. 1987, 30, 635. doi: 10.1021/jm00387a009

    8. [8]

      Chaffmann, M.; Brogden, R. N. Drugs 1985, 29, 387 doi: 10.2165/00003495-198529050-00001

    9. [9]

      Kawakita, S.; Kinoshita, M.; Ishikawa, H.; Kagoshima, T.; Ka-tori, R.; Ishikawa, K.; Hirota, Y. Clin. Cardiol. 1991, 14, 53. doi: 10.1002/clc.4960140112

    10. [10]

      Dreyfuss, J.; Cohen, A. I.; Hess, S. M. J. Pharm. Sci. 1968, 57, 1505. doi: 10.1002/jps.2600570907

    11. [11]

      冯志颖, 王中刚, 精神医学杂志, 2010, 23, 475.Feng, Z. Y.; Wang, Z. G. J. Psychiatry 2010, 23, 475(in Chinese). doi: 10.3969/j.issn.1009-7201.2010.06.031

    12. [12]

      Farzana, L. A.; Fatima, I.; Ihsan-ul-Haq.; Bushra, M.; Mohammad, B.; Umer, R. Bioorg. Med. Chem. 2008, 16, 7691 doi: 10.1016/j.bmc.2008.07.009

    13. [13]

      Roberto, D. S.; Roberta, C. Farmaco 2005, 60, 385. doi: 10.1016/j.farmac.2005.03.006

    14. [14]

      Satyanarayana, K.; Rao, M. N. A. Indian J. Pharm. Sci. 1993, 55, 230.

    15. [15]

      Urbanski, M. J.; Chen, R. H.; Demarest, K. T.; Gunnet, J.; Look, R.; Ericson, E.; Murray, W. V.; Rybczynski, P. J.; Zhang, X. Y. Bioorg. Med. Chem. Lett. 2003, 13, 4031. doi: 10.1016/j.bmcl.2003.08.051

    16. [16]

      Arya, K.; Dandia, A. Bioorg. Med. Chem. Lett. 2008, 18, 114. doi: 10.1016/j.bmcl.2007.11.002

    17. [17]

      Satbir, M.; Savita, N.; Suchita, S.; Mohini, K.; Gurdeep, S.; Vi-render, S. J. Heterocycl. Chem. 2017, 54, 3282. doi: 10.1002/jhet.2948

    18. [18]

      张静, 穆博帅, 吴萌, 边彦青, 李媛, 高等学校化学学报, 2015, 36, 687.Zhang, J.; Mu, B. S.; Wu, M.; Bian, Y. Q.; Li, Y. Chem. J. Chin. Univ. 2015, 36, 687(in Chinese).

    19. [19]

      Kamal, A.; Shankaraiah, N.; Devaiah, V.; Reddy, K. L.; Juvekar, A.; Sen, S.; Kurian, N.; Zingde, S. Bioorg. Med. Chem. Lett. 2008, 18, 1468. doi: 10.1016/j.bmcl.2007.12.063

    20. [20]

      Buckler, R. T.; Hartzler, H. E.; Kurchacova, E.; Nichols, G.; Phillips, B. M. J. Med. Chem. 1978, 21, 1254. doi: 10.1021/jm00210a015

    21. [21]

      Kim, S.; Cho, S. N.; Oh, T.; Kim, P. Bioorg. Med. Chem. Lett. 2012, 22, 6844. doi: 10.1016/j.bmcl.2012.09.041

    22. [22]

      Dorota, G. P.; Jan, B.; Iwona, E. G. Eur. J. Med. Chem. 2012, 47, 501. doi: 10.1016/j.ejmech.2011.11.021

    23. [23]

      Aher, N. G.; Pore, V. S.; Mishra, N. N.; Kumar, A.; Shukla, P. K.; Sharma, A.; Bhat, M. K. Bioorg. Med. Chem. Lett. 2009, 19, 759. doi: 10.1016/j.bmcl.2008.12.026

    24. [24]

      郭新乐, 于志, 鄢笑非, 高川, 国外医药抗生素分册, 2018, 39, 286.Guo, X. L.; Yu, Z.; Yan, X. F.; Gao, C. World Notes Antibiot. 2018, 39, 286(in Chinese). doi: 10.3969/j.issn.1001-8751.2018.04.004

    25. [25]

      王岩, 孔令满, 王冉冉, 田克情, 张萍, 有机化学, 2019, 39, 2663.Wang, Y.; Kong, L. M.; Wang, R. R.; Tian, K. Q.; Zhang, P. Chin. J. Org. Chem. 2019, 39, 2663(in Chinese). 

    26. [26]

      Shunsaku, O.; Ikuo, K.; Takahiro, U.; Masayuki, Y.; Tomomichi, Y.; Satoshi, Y. Chem. Pharm. Bull. 1997, 45, 1140. doi: 10.1248/cpb.45.1140

    27. [27]

      Joule J. A.; Mills K. Heterocyclic Chemistry, John Wiley & Sons Ltd, UK, 2010, p. 557.

    28. [28]

      孔令满, 硕士论文, 河北师范大学, 石家庄, 2017.Kong, L. M. M.S. Thesis, Hebei Normal University, Shijiazhuang, 2017 (in Chinese). 

    29. [29]

      Wang, L. Z.; Zhang, P.; Zhang, X. M.; Zhang, Y. H.; Li, Y.; Wang, Y. X. Eur. J. Med. Chem. 2009, 44, 2815. doi: 10.1016/j.ejmech.2008.12.021

  • 图式 1  化合物的合成路线5a~5f、6a~6f7a~7f

    Scheme 1  Synthetic route of compounds 5a~5f、6a~6f and 7a~7f

    图 1  化合物7e的晶体结构

    Figure 1  Crystal structure of compound 7e

    表 1  化合物5a~5f, 6a~6f7a~7f的抑真菌活性(抑菌圈直径/mm)a, b

    Table 1.  Antifungal activity of compounds 5a~5f, 6a~6f and 7a~7f (diameter of inhibition zone/mm)

    Compd. R C. neoformans stand C. neoformans clinical C. albicans
    5a H 16.39 17.08 16.21
    5b F 16.95 16.49 15.56
    5c Cl 12.65 12.29 9.73
    5d Br 12.45 12.23 6.00
    5e CH3 6.00 6.00 6.00
    5f OCH3 19.44 19.19 14.26
    6a H 6.00 6.00 6.00
    6b F 6.00 6.00 6.00
    6c Cl 6.00 6.00 6.00
    6d Br 6.00 6.00 6.00
    6e CH3 6.00 6.00 6.00
    6f OCH3 6.00 6.00 6.00
    7a H 6.00 6.00 6.00
    7b F 6.00 6.00 6.00
    7c Cl 6.00 6.00 6.00
    7d Br 6.00 6.00 6.00
    7e CH3 6.00 6.00 6.00
    7f OCH3 6.00 6.00 6.00
    Fluconazol 22.40 22.40 20.20
    a All values were measured with 200 μg of the tested compound/disk. b The diameter of the filter paper is 6.00 mm, zone of inhibition 6.00 mm considers as no antibacterial activity.
    下载: 导出CSV

    表 2  化合物5a、5b5f对新生隐球菌(C. neoformans)的MIC80和MFC数据(μg/mL)

    Table 2.  MIC80 and MFC values (μg/mL) of compounds 5a, 5b and 5f to C. neoformans

    Compd. R MIC80 MFC
    ATCC34874 Clinical isolate ATCC34874 Clinical isolate
    5a H 4.5 4.5 83.0 81.0
    5b F 4.0 4.0 82.0 82.0
    5f OCH3 3.0 3.5 69.0 69.0
    Fluconazol 2.0 3.0 >128.0 >128.0
    下载: 导出CSV
  • 加载中
计量
  • PDF下载量:  1
  • 文章访问数:  131
  • HTML全文浏览量:  12
文章相关
  • 发布日期:  2020-02-25
  • 收稿日期:  2019-07-31
  • 修回日期:  2019-10-05
  • 网络出版日期:  2019-02-25
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

/

返回文章