C(3)-1, 2, 4-三氮唑取代的1, 5-苯并硫氮杂䓬的合成及抑菌活性

引用本文: 王岩, 孔令满, 王冉冉, 田克情, 张萍. C(3)-1, 2, 4-三氮唑取代的1, 5-苯并硫氮杂䓬的合成及抑菌活性[J]. 有机化学, 2019, 39(9): 2663-2670. doi: 10.6023/cjoc201901041 shu

Citation: Wang Yan, Kong Lingman, Wang Ranran, Tian Keqing, Zhang Ping. Synthesis and Antimicrobial Activity of C(3)-1, 2, 4-Triazolyl-1, 5-benzothiazepines[J]. Chinese Journal of Organic Chemistry, 2019, 39(9): 2663-2670. doi: 10.6023/cjoc201901041 shu

C(3)-1, 2, 4-三氮唑取代的1, 5-苯并硫氮杂䓬的合成及抑菌活性

王岩 ^a, ,
孔令满 ^a, ,
王冉冉 ^a, ,
田克情 ^b, ,
张萍 ^{a,
,}

a.
河北师范大学化学与材料科学学院石家庄 050024
b.
河北化工医药职业技术学院化学与环境工程系石家庄 050026

通讯作者: 张萍, zhangpingp@sina.com

基金项目:

河北省自然科学基金（No.B2017205100）及河北师范大学研究生创新基金（No.CXZZSS201804）资助项目

摘要: 设计合成了3类C（3）-1，2，4-三氮唑取代的1，5-苯并硫氮杂䓬化合物，2，3-二氢/2，5-二氢/2，3，4，5-四氢-3-（1，2，4-三氮唑）-4-芳基-1，5-苯并硫氮杂䓬.研究了中间体及目标产物的合成条件，确定了其中2个副产物的结构.目标产物的抑菌活性测试表明，2，3-二氢/2，5-二氢-3-（1，2，4-三氮唑）-4-芳基-1，5-苯并硫氮杂䓬对新生隐球菌和白色念珠菌表现出很高的抑制作用，在200 μg/disc的浓度下，有4个化合物对新生隐球菌的抑制作用高于对照药物氟康唑，有3个化合物对白色念珠菌的抑制活性高于对照药物氟康唑.初步抑真菌构效关系研究表明，1，2，4-三氮唑环和C=N双键是2，3-二氢-3-（1，2，4-三氮唑）-4-芳基-1，5-苯并硫氮杂䓬抑真菌活性的关键药效团.

关键词:

English

Synthesis and Antimicrobial Activity of C(3)-1, 2, 4-Triazolyl-1, 5-benzothiazepines

a.
College of Chemistry and Materials Science, Hebei Normal University, Shijiazhuang 050024
b.
Environment and Chemical Engineering, Hebei Chemical and Pharmaceutical College, Shijiazhuang 050026

Corresponding author: Zhang, Ping, E-mail: zhangpingp@sina.com

Received Date: 25 January 2019
Revised Date: 01 April 2019
Available Online: 25 September 2019
Fund Project:

Project supported by the Natural Science Foundation of Hebei Province (No. B2017205100) and the Graduate Student Innovation Fundation of Hebei Normal University (No. CXZZSS201804)

Abstract: Three kinds of C(3)-1, 2, 4-triazolyl-1, 5-benzothiazepines, 2, 3-dihydro/2, 5-dihydro/2, 3, 4, 5-tetrahydro-3-(1, 2, 4-tria-zolyl)-4-aryl-1, 5-benzothiazepines, were designed and synthesized. The synthesis conditions of intermediates and target products were studied, and the structures of two by-products were determined. The antimicrobial activity test of the target products showed that 2, 3-dihydro/2, 5-dihydro-3-(1, 2, 4-triazolyl)-4-aryl-1, 5-benzothiazepines exhibited high inhibitory effects on C. neoformans and C. albicans. At concentration of 200 μg/disc, the inhibitory effects of four compounds on C. neoformans were stronger than that of fluconazol, and the inhibitory effects of three compounds on C. albicans were stronger than that of fluconazol. The preliminary study on the structure-activity relationship of antifungal revealed that 1, 2, 4-triazolyl and C=N double bond were the key function groups in the antifungal activity of 2, 3-dihydro-3-(1, 2, 4-triazolyl)-4-aryl-1, 5-benzothiazepines.

Key words:

1, 2, 4-三氮唑是含有三个氮原子的五元杂环化合物, 具有较强的络合金属离子和形成氢键的能力, 因而在药物化学领域备受关注, 表现出抗肿瘤^[1]、抗结核^[2]、抗丙肝^[3]、抗菌^[4]等多种生物活性, 如临床抗真菌药物氟康唑(fluconazole)^[5]、艾沙康唑(isavuconazole)^[6]及持续占据销售榜首的三唑类杀菌剂环丙唑醇都含有1, 2, 4-三氮唑结构^[7].苯并硫氮杂䓬是含硫和氮原子的七元杂环和苯环的并合体系, 该结构骨架广泛存在于多种药物分子和天然产物中, 是合成化学和药物化学关注的热点, 该骨架的衍生物地尔硫䓬(diltiazem)^[8]、克仑硫䓬(clentiazem)^[9]在临床上用于治疗心脑血管疾病, 硫西新(thiazesim)^[10]、喹硫平(quetiapine)^[11]和氯噻平(clotiapine)^[12]等用于治疗精神类疾病(图 1).除此之外, 此类化合物还具有较好的抗菌^[13]、消炎^[14]、抗肿瘤^[15]以及抗血小板凝聚^[16]等活性.本课题组围绕抑菌活性, 设计合成了多个系列的苯并硫氮杂䓬衍生物^[17~19].考虑到1, 2, 4-三氮唑结构良好的抑菌能力, 按照活性拼接原理, 前期的工作将1, 2, 4-三氮唑环引入苯并硫氮杂䓬七元杂环的2位, 所合成的2-(1, 2, 4-三氮唑)-4-芳基-1, 5-苯并硫氮杂䓬对真菌具有中度的抑制作用^[20].为了考察1, 2, 4-三氮唑环在七元杂环的3位对抑菌活性的影响, 继续寻找高抑菌活性的化合物, 本文首次设计合成了3类3-(1, 2, 4-三氮唑)-4-芳基-1, 5-苯并硫氮杂䓬, 合成路线见Scheme 1.测试了它们对真菌(新生隐球菌标准株、新生隐球菌临床株、白色念珠菌)和细菌(大肠杆菌、金黄色葡萄球菌)的抑制作用, 并进行初步的构效关系分析.

图 1

图 1. 地尔硫䓬、喹硫平及氯噻平的结构

Figure 1. Structures of diltiazem, quetiapine and clotiapine

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图式 1

图式 1. 化合物的合成路线

Scheme 1. Synthetic route of compounds

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1. 结果与讨论

1.1 目标化合物的合成研究

化合物2a~2f的合成按照文献[21]方法, 反应进行到20 min生成目标产物2a(以2a为例), 2 h时观察到原料1a和目标产物2a发生迈克尔加成反应的产物7, 7的含量主要受反应时间的影响, 综合考虑反应效果, 最佳反应时间为4 h. 2a~2f的结构表征和文献[21, 22]一致, 化合物7未见文献报道.

化合物3a~3f的合成在二氯甲烷和甲苯溶剂中反应时间长且原料转化率低, 在甲醇溶剂中反应4 h, 3a~3f的产率在78%~88%之间, 生成目标物的同时观察到少量的副产物8(以3a为例), 经波谱数据分析可知, 8是甲醇和2a发生迈克尔加成反应所得, 将反应温度降低至冰水浴, 8的含量明显降低, 3a~3f和化合物8未见文献报道.

化合物3a~3f在对甲基苯磺酸(PTS)的催化下分子内亲核加成再消除, 同时生成4a~4f和5a~5f, 且二者产率接近, 反应1 h原料转化趋于完全. 4a~4f和5a~5f可以被NaBH₃CN还原为6a~6f, 实验中发现, 4a~4f的还原比5a~5f所需温度低, 时间明显短, 原因可能是^[23]5a~5f在还原过程中先异构化为4a~4f, 进而再被NaBH₃CN还原.

1.2 目标化合物的抑菌活性及抑真菌构效关系分析

测试了目标化合物4a~4f, 5a~5f和6a~6f对新生隐球菌标准株(C. neoformans stand)、新生隐球菌临床株(C. neoformans clinical)、白色念珠菌(C. albicans)、金黄色葡萄球菌(S. aureus)和大肠杆菌(E. coli)的抑制作用, 抑菌活性数据见表 1.由表 1可知, 合成的12个C(3)-1, 2, 4-三氮唑取代的2, 3/2, 5-二氢-1, 5-苯并硫氮杂䓬4a~4f, 5a~5f对新生隐球菌(C. neoformans)具有很高的抑制作用, 其中对新生隐球菌标准株(C. neoformans stand)的抑制活性除4f, 5c, 5d外均略高于新生隐球菌临床株(C. neoformans clinical), 属于该真菌的高度敏感化合物, 在200 µg/disc的浓度下, 4a, 4b, 4e, 5c对新生隐球菌(C. neoformans)的抑制作用高于对照药物氟康唑; 4a~4f, 5a~5f对白色念珠菌(C. albicans)呈现了中到高度的抑制.对于抑真菌活性突出的化合物4a, 4b, 4e和5c, 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, 4a, 4b, 4e和5c的MIC₈₀与抗真菌药氟康唑相近, MFC也都低于氟康唑. C(3)-1, 2, 4-三氮唑取代的2, 3/2, 5-二氢-1, 5-苯并硫氮杂䓬有可能成为一类具有良好应用前景的抑真菌化合物.

表 1

表 1 化合物4a~4f, 5a~5f和6a~6f的抑菌活性(抑菌圈直径/mm)^a^, ^b

Table 1. Antimicrobial activity of compounds 4a~4f, 5a~5f and 6a~6f (diameter of inhibition zone/mm)

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Compd.	R	C. neoformans stand	C. neoformans clinical	C. albicans	S. aureus	E. coli
4a	H	29.30	28.37	25.93	17.00	15.57
4b	F	27.47	25.80	20.47	17.30	14.83
4c	Cl	21.10	20.30	15.20	13.17	11.63
4d	Br	17.50	17.33	15.20	12.10	10.03
4e	CH₃	25.63	25.30	22.67	14.17	12.63
4f	OCH₃	21.33	22.97	17.87	14.03	13.00
5a	H	23.43	18.63	20.03	16.53	14.97
5b	F	21.40	16.67	15.30	9.33	7.63
5c	Cl	26.43	26.60	12.93	11.13	10.17
5d	Br	21.93	23.10	10.00	8.67	8.93
5e	CH₃	18.33	17.33	15.43	8.67	8.73
5f	OCH₃	19.87	17.40	18.67	16.13	16.47
6a	H	6.00	6.00	6.00	6.00	6.00
6b	F	6.00	6.00	6.00	6.00	6.00
6c	Cl	23.67	23.66	6.00	6.00	6.00
6d	Br	20.80	20.51	6.00	6.00	6.00
6e	CH₃	6.00	6.00	6.00	6.00	6.00
6f	OCH₃	6.00	6.00	6.00	6.00	6.00
Fluconazol	—	22.40	22.40	20.20	—	—
Ciprofloxacin hydrochloride	—	—	—	—	21.60	21.60
^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 consider as no antibacterial activity.

表 2

表 2 化合物4a, 4b, 4e和5c的MIC₈₀和MFC数据

Table 2. MIC₈₀ and MFC values of compounds 4a, 4b, 4e and 5c

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Compd.	R	MIC₈₀/(µg•mL^－1)		MFC/(µg•mL^－1)
Compd.	R	ATCC34874	Clinical isolate	ATCC34874	Clinical isolate
4a	H	2.0	2.0	65.0	71.0
4b	F	2.0	2.0	72.0	74.0
4e	CH₃	3.0	3.0	58.0	58.0
5c	Cl	3.0	3.0	73.0	77.0
Fluconazol	—	2.0	3.0	＞128.0	＞128.0

针对化合物4a~4f的抑真菌活性, 结合课题组前面的工作, 可得如下初步的构效关系: 3位不含1, 2, 4-三氮唑取代的化合物9a~9f对新生隐球菌没有抑制作用^[24], 说明3位上的1, 2, 4-三氮唑是引起4a~4f活性的关键药效团, 且1, 2, 4-三氮唑连接在1, 5-苯并硫氮杂䓬的3位比在2位更有利于抑真菌活性的提高. 4位苯环上的取代基对抑真菌活性有不同程度的影响, 值得关注的是当苯环上取代基为氢(4a)或氟(4b)时抑真菌效果最好, 具有开发为有效抑真菌物质的前景.为了了解4a~4f中C＝N双键结构对抑真菌活性的影响, 还研究了不具有C＝N双键的6a~6f对新生隐球菌的抑制作用(表 1), 由表 1数据可知, 除6c和6d保持了对新生隐球菌的高度抑制外, 其余4个化合物活性消失, 说明C＝N双键结构单元和3位上的1, 2, 4-三氮唑环是4a~4f抑真菌的关键条件, 苯环上的取代基对活性也有一定的影响, 还需进一步深入研究.

化合物4a~4f, 5a~5f不仅对真菌表现出优异的抑制作用, 对两种细菌的抑制效果也非常显著, 大部分化合物对金黄色葡萄球菌和大肠杆菌有中到高度的抑制, 其中4a, 4b, 5a和5f对金黄色葡萄球菌、5f对大肠杆菌有高度抑制, 课题组之前合成的对真菌有抑制作用的化合物, 对细菌普遍没有作用, 本工作的这一发现为抗细菌药物结构的筛选提供了有价值的参考.

2. 结论

设计合成了18个C(3)-1, 2, 4-三氮唑取代的1, 5-苯并硫氮杂䓬化合物, 并进行了抑菌活性测试和初步构效关系的分析, 发现了对新生隐球菌、白色念珠菌抑制效果优异的新化合物, 具有潜在的临床应用价值.确定了1, 2, 4-三氮唑环和C＝N双键结构单元是影响4a~4f抑真菌活性的关键基团, 研究结果为杂䓬类化合物的构效关系以及筛选高抑菌活性的化合物提供了有价值的参考.

3. 实验部分

3.1 仪器与试剂

Thermo SCIENTIFIC型红外光谱仪, KBr压片法; Agilent Technologies LC/MS 1200 series-6130Quadrupole型液质联用仪; WIPM-NMR-400M型核磁共振仪, AVANCEII-500M型核磁共振仪, TMS为内标.

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、新生隐球菌临床株、白色念珠菌、金黄色葡萄球菌、大肠杆菌由河北师范大学生命科学学院提供.

3.2 实验方法

3.2.1 1-芳基-2-(1, 2, 4-三氮唑)-2-丙烯-1-酮(2a~2f)的合成

在50 mL三口瓶中依次加入1a~1f (11 mmol)、15 mL乙腈、0.3 g (11 mmol)多聚甲醛、1.4 g (17 mmol)二甲胺盐酸盐和适量盐酸至pH值在3~4之间.回流反应4 h, 冷却, 减压浓缩溶剂, 依次加入二氯甲烷和饱和碳酸氢钠水溶液调节pH值至中性, 分液, 有机相用无水硫酸钠干燥, 减压浓缩溶剂, 剩余物经硅胶柱层析[V(石油醚):V(乙酸乙酯)＝2:1]得到化合物2a~2f和7.

1, 5-二苯基-2, 4-二-(1, 2, 4-三氮唑)-1, 5-戊二酮(7):无色油状液体, 产率14%. ¹H NMR (CDCl₃, 500 MHz) δ: 8.36 (s, 2H), 8.26 (s, 1H), 8.16 (s, 2H, ), 7.92 (s, 1H), 8.00~7.47 (m, 15H), 6.04 (t, J＝7.5 Hz, 1H), 5.84 (dd, J＝6.5, 8.5 Hz, 2H), 3.46~3.40 (m, J＝7.5 Hz, 0.5H), 3.14 (dd, J＝6.5, 8.5 Hz, 2H), 2.76~2.70 (m, J＝7.5 Hz, 0.5H); ¹³C NMR(CDCl₃, 125 MHz) δ: 192.6, 152.4, 152.1, 144.5, 143.5, 134.6, 134.5, 133.7, 133.3, 129.2, 128.8, 128.6, 60.4, 34.5; HRMS calcd for C₂₁H₁₉N₆O₂ [M+H]⁺ 387.1564, found 387.1561.

3.2.2 1-芳基-2-(1, 2, 4-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(3a~3f)的合成

在50 mL三口瓶中依次加入2a~2f (5 mmol)、0.63 g (5 mmol) 2-氨基苯硫酚和10 mL无水甲醇, 冰水浴下反应4 h, 减压浓缩溶剂, 剩余物经硅胶柱层析[V(石油醚):V(乙酸乙酯)＝2:1]得到化合物3a~3f和8.

1-苯基-2-(1, 2, 4-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(3a):黄色油状液体, 产率88%. ¹H NMR (400 MHz, CDCl₃) δ: 8.33 (s, 1H), 7.97 (s, 1H), 7.68~6.72 (m, 9H), 6.01 (dd, J_XA＝4.4 Hz, J_XB＝9.6 Hz, 1H), 4.39 (s, 2H), 3.60 (dd, J_AX＝4.4 Hz, J_AB＝14.4 Hz, 1H), 3.36 (dd, J_BA＝14.4 Hz, J_BX＝9.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 192.5, 151.6, 149.0, 143.6, 137.0, 134.4, 133.8, 131.2, 129.0, 128.9, 128.8, 128.7, 119.0, 115.4, 114.8, 62.8, 36.3; HRMS calcd for C₁₇H₁₇N₄OS [M+H]⁺ 325.1118, found 325.1115.

1-(4-氟苯基)-2-(1, 2, 4-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(3b):黄色油状液体, 产率85%. ¹H NMR (400 MHz, CDCl₃) δ: 8.32 (s, 1H), 7.97 (s, 1H), 7.72~6.75 (m, 8H), 5.96 (dd, J_XA＝4.4 Hz, J_XB＝9.4 Hz, 1H), 4.39 (s, 2H), 3.58 (dd, J_AX＝4.4 Hz, J_AB＝14.4 Hz, 1H), 3.35 (dd, J_BA＝14.4 Hz, J_BX＝9.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 190.9, 166.3, (d, ¹J_CF＝256.7 Hz), 151.7, 149.0, 143.5, 137.1, 131.6, 130.2, 119.0, 115.4, 114.8, 62.7, 36.2; HRMS calcd for C₁₇H₁₆N₄OFS [M+H]⁺ 343.1023, found 343.1021.

1-(4-氯苯基)-2-(1, 2, 4-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(3c):黄色油状液体, 产率85%. ¹H NMR (400 MHz, CDCl₃) δ: 8.32 (s, 1H), 7.97 (s, 1H), 7.59~6.72 (m, 8H), 5.94 (dd, J_XA＝4.4 Hz, J_XB＝9.6 Hz, 1H), 4.41 (s, 2H), 3.57 (dd, J_AX＝4.4 Hz, J_AB＝14.2 Hz, 1H), 3.34 (dd, J_BA＝14.4 Hz, J_BX＝9.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 191.3, 151.7, 149.0, 143.4, 137.1, 132.1, 131.3, 130.1, 130.0, 129.4, 129.3, 119.0, 115.5, 114.7, 62.8, 36.1; HRMS calcd for C₁₇H₁₆N₄OSCl [M+H]⁺ 359.0728, found 359.0724.

1-(4-溴苯基)-2-(1, 2, 4-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(3d):黄色油状液体, 产率79%. ¹H NMR (400 MHz, CDCl₃) δ: 8.32 (s, 1H), 7.97 (s, 1H), 7.52~6.72 (m, 8H), 5.93 (dd, J_XA＝4.4 Hz, J_XB＝9.4 Hz, 1H), 4.18 (s, 2H), 3.57 (dd, J_AX＝4.4 Hz, J_AB＝14.4 Hz, 1H), 3.34 (dd, J_BA＝14.4 Hz, J_BX＝9.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 191.7, 151.7, 149.0, 143.5, 137.1, 132.5, 132.4, 131.3, 130.1, 129.8, 119.0, 115.4, 114.6, 62.8, 36.1; HRMS calcd for C₁₇H₁₆N₄OSBr [M+H]⁺ 403.0223, found 403.0220.

1-(4-甲基苯基)-2-(1, 2, 4-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(3e):黄色油状液体, 产率81%. ¹H NMR (400 MHz, CDCl₃) δ: 8.33 (s, 1H), 7.96 (s, 1H), 7.56~6.70 (m, 8H), 5.99 (dd, J_XA＝4.4 Hz, J_XB＝9.8 Hz, 1H), 4.44 (s, 2H), 3.58 (dd, J_AX＝4.4 Hz, J_AB＝14.4 Hz, 1H), 3.33 (dd, J_BA＝14.2 Hz, J_BX＝9.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 191.9, 151.6, 149.1, 145.6, 143.5, 137.1, 131.2, 129.8, 129.7, 128.9, 128.8, 118.6, 115.2, 114.6, 62.8, 36.4, 21.7; HRMS calcd for C₁₈H₁₉N₄OS [M+H]⁺ 339.1274, found 339.1271.

1-(4-甲氧基苯基)-2-(1, 2, 4-三氮唑)-3-(2-氨基苯硫基)-1-丙酮(3f):黄色油状液体, 产率78%. ¹H NMR (400 MHz, CDCl₃) δ: 8.35 (s, 1H), 7.99 (s, 1H), 7.71~6.75 (m, 8H), 6.01 (dd, J_XA＝4.4 Hz, J_XB＝9.6 Hz, 1H), 4.18 (s, 2H), 3.88 (s, 3H), 3.61 (dd, J_AX＝4.4 Hz, J_AB＝14.4 Hz, 1H), 3.37 (dd, J_BA＝14.4 Hz, J_BX＝9.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 190.8, 164.5, 151.5, 149.0, 143.4, 137.0, 131.2, 126.7, 118.9, 115.4, 114.9, 114.3, 62.5, 55.6, 36.6; HRMS calcd for C₁₈H₁₉N₄O₂S [M+H]⁺ 355.1223, found 355.1221.

1-苯基-2-(1, 2, 4-三氮唑)-3-甲氧基-1-丙酮(8):白色固体, 产率7%. m.p. 152~154 ℃; ¹H NMR (CDCl₃, 500 MHz) δ: 8.47 (s, 1H), 7.94 (s, 1H), 7.96~7.49 (m, 5H), 6.23 (t, J_XA＝6.0 Hz, J_XB＝4.3 Hz, 1H), 4.06 (dd, J_AX＝6.0 Hz, J_AB＝7.5 Hz, 1H), 4.01 (dd, J_BX＝4.3 Hz, J_BA＝7.5 Hz, 1H), 3.32 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ: 192.1, 151.3, 144.3, 134.4, 134.3, 129.1, 128.5, 71.8, 64.3, 59.4; HRMS calcd for C₁₂H₁₄N₃O₂ [M+H]⁺ 232.1081, found 232.1081.

3.2.3 3-(1, 2, 4-三氮唑)-4-芳基-2, 3/2, 5-二氢-1, 5-苯并硫氮杂䓬4a~4f和5a~5f的合成

在50 mL单口瓶中加入3a~3f (1.6 mmol)、10 mL甲苯和适量对甲基苯磺酸(PTS), 加热回流分水1 h, 将反应液冷却至室温, 减压浓缩溶剂, 加入二氯甲烷和饱和碳酸氢钠水溶液调节pH值至中性, 分液, 有机相用无水硫酸钠干燥后浓缩, 剩余物经硅胶柱层析[V(二氯甲烷):V(甲醇)＝100:1]得到化合物4a~4f和5a~5f.

3-(1, 2, 4-三氮唑)-4-苯基-2, 3-二氢-1, 5-苯并硫氮杂䓬(4a):黄色油状液体, 产率40%. ¹H NMR (CDCl₃, 500 MHz) δ: 7.86 (s, 1H), 7.82 (s, 1H), 7.63~7.12 (m, 9H), 5.69 (dd, J_XA＝10.5 Hz, J_XB＝6.5 Hz, 1H), 4.28 (dd, J_AX＝10.5 Hz, J_AB＝12.3 Hz, 1H), 4.19 (dd, J_BA＝12.3 Hz, J_BX＝6.5 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ: 167.7, 151.4, 150.3, 143.1, 136.3, 134.4, 130.7, 130.3, 128.5, 127.4, 126.1, 125.6, 122.7, 60.4, 43.1; IR (KBr) ν: 1628 cm^－1; HRMS calcd for C₁₇H₁₅N₄S [M+H]⁺ 307.1012, found 307.1010.

3-(1, 2, 4-三氮唑)-4-(4-氟苯基)-2, 3-二氢-1, 5-苯并硫氮杂䓬(4b):黄色油状液体, 产率38%. ¹H NMR (CDCl₃, 500 MHz) δ: 7.88 (s, 1H), 7.85 (s, 1H), 7.63~7.00 (m, 8H), 5.66 (dd, J_XA＝10.5 Hz, J_XB＝6.5 Hz, 1H), 4.27 (dd, J_AX＝10.5 Hz, J_AB＝12.5 Hz, 1H), 4.18 (dd, J_BA＝12.5 Hz, J_BX＝6.5 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ: 166.3, 150.8 (d, ¹J_CF＝174.6 Hz), 143.2, 132.4 (d, ⁴J_CF＝3.4 Hz), 130.4, 129.7 (d, ³J_CF＝8.5 Hz), 126.1, 125.6, 122.8, 115.6 (d, ²J_CF＝21.0 Hz), 60.3, 43.0; IR (KBr) ν: 1599 cm^－1; HRMS calcd for C₁₇H₁₄N₄FS [M+H]⁺ 325.0918, found 325.0916.

3-(1, 2, 4-三氮唑)-4-(4-氯苯基)-2, 3-二氢-1, 5-苯并硫氮杂䓬(4c):黄色油状液体, 产率34%. ¹H NMR (CDCl₃, 500 MHz) δ: 7.87 (s, 1H), 7.84 (s, 1H), 7.63~7.13 (m, 8H), 5.66 (dd, J_XA＝10.5 Hz, J_XB＝6.5 Hz, 1H), 4.22 (dd, J_AX＝10.5 Hz, J_AB＝12.5 Hz, 1H), 4.16 (dd, J_BA＝11.8 Hz, J_BX＝6.5 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ: 166.3, 151.6, 150.0, 143.2, 137.0, 134.6, 134.4, 130.4, 128.8, 128.7, 126.3, 125.8, 122.9, 60.3, 43.0; IR (KBr) ν: 1588 cm^－1; HRMS calcd for C₁₇H₁₄N₄ClS [M+H]⁺ 341.0622, found 341.0618.

3-(1, 2, 4-三氮唑)-4-(4-溴苯基)-2, 3-二氢-1, 5-苯并硫氮杂䓬(4d):黄色油状液体, 产率32%. ¹H NMR (CDCl₃, 500 MHz) δ: 7.88 (s, 1H), 7.85 (s, 1H), 7.63~7.14 (m, 8H), 5.66 (dd, J_XA＝10.5 Hz, J_XB＝6.5 Hz, 1H), 4.24 (dd, J_AX＝10.5 Hz, J_AB＝12.5 Hz, 1H), 4.17 (dd, J_BA＝12.5 Hz, J_BX＝6.5 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ: 165.4, 150.7, 149.0, 142.3, 134.2, 133.4, 131.2, 130.8, 129.5, 128.9, 128.1, 124.9, 122.0, 59.3, 42.1; IR (KBr) ν: 1607 cm^－1; HRMS calcd for C₁₇H₁₄N₄SBr [M+H]⁺ 385.0117, found 385.0116.

3-(1, 2, 4-三氮唑)-4-(4-甲基苯基)-2, 3-二氢-1, 5-苯并硫氮杂䓬(4e):黄色油状液体, 产率37%. ¹H NMR (CDCl₃, 500 MHz) δ: 7.84 (s, 1H), 7.81 (s, 1H), 7.60~7.08 (m, 8H), 5.65 (dd, J_XA＝10.5 Hz, J_XB＝6.5 Hz, 1H), 4.24 (dd, J_AX＝10.5 Hz, J_AB＝12.3 Hz, 1H), 4.15 (dd, J_BA＝12.3 Hz, J_BX＝6.5 Hz, 1H), 2.33 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ: 167.3, 151.3, 150.4, 143.2, 141.1, 134.3, 133.5, 130.3, 129.2, 127.3, 125.8, 125.5, 122.8, 60.3, 43.0, 21.3; IR (KBr) ν: 1606 cm^－1; HRMS calcd for C₁₈H₁₇N₄S [M+H]⁺ 321.1168, found 321.1168.

3-(1, 2, 4-三氮唑)-4-(4-甲氧基苯基)-2, 3-二氢-1, 5-苯并硫氮杂䓬(4f):黄色油状液体, 产率37%. ¹H NMR (CDCl₃, 500 MHz) δ: 6.98 (s, 1H), 6.93 (s, 1H), 6.70~6.19 (m, 8H), 4.76 (dd, J_XA＝14.5 Hz, J_XB＝6.5 Hz, 1H), 3.35 (dd, J_AX＝14.5 Hz, J_AB＝16.3 Hz, 1H), 3.26 (dd, J_BA＝16.3 Hz, J_BX＝6.5 Hz, 1H), 2.90 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ: 164.4, 159.6, 149.2, 148.5, 141.2, 132.2, 128.1, 127.1, 123.9, 120.7, 111.8, 58.6, 53.3, 40.8; IR (KBr) ν: 1609 cm^－1; HRMS calcd for C₁₈H₁₇N₄OS [M+H]⁺ 337.1118, found 337.1115.

3-(1, 2, 4-三氮唑)-4-苯基-2, 5-二氢-1, 5-苯并硫氮杂䓬(5a):黄色油状液体, 产率42%. ¹H NMR (CDCl₃, 500 MHz) δ: 7.89 (s, 1H), 7.48 (s, 1H), 7.42~6.87 (m, 9H), 6.04 (s, 1H), 3.87 (s, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ: 152.0, 145.0, 143.5, 139.9, 137.1, 133.6, 129.5, 129.0, 128.2, 128.1, 125.8, 121.8, 121.1, 114.1, 37.4; IR (KBr) ν: 3322, 1667 cm^－1; HRMS calcd for C₁₇H₁₅N₄S [M+H]⁺ 307.1012, found 307.1005.

3-(1, 2, 4-三氮唑)-4-(4-氟苯基)-2, 5-二氢-1, 5-苯并硫氮杂䓬(5b):黄色油状液体, 产率40%. ¹H NMR (CDCl₃, 500 MHz) δ: 7.91 (s, 1H), 7.50 (s, 1H), 7.43~6.86 (m, 8H), 5.89 (s, 1H), 3.85 (s, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ: 152.2, 144.1 (d, ¹J_CF＝206.9 Hz), 139.1, 133.7, 130.1 (d, ³J_CF＝8.3 Hz), 128.3, 125.8, 122.0, 121.1, 116.2 (d, ²J_CF＝21.0 Hz), 114.4, 37.4; IR (KBr) ν: 3300, 1640 cm^－1; HRMS calcd for C₁₇H₁₄N₄FS [M+H]⁺ 325.0918, found 325.0911.

3-(1, 2, 4-三氮唑)-4-(4-氯苯基)-2, 5-二氢-1, 5-苯并硫氮杂䓬(5c):黄色油状液体, 产率36%. ¹H NMR (CDCl₃, 500 MHz) δ: 7.92 (s, 1H), 7.51 (s, 1H), 7.43~6.85 (m, 8H), 5.86 (s, 1H), 3.85 (s, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ: 152.3, 144.9, 143.2, 138.9, 133.7, 129.5, 129.3, 128.3, 122.1, 121.1, 114.6, 37.4; IR (KBr) ν: 3157, 1640 cm^－1; HRMS calcd for C₁₇H₁₄N₄ClS [M+H]⁺ 341.0622, found 341.0616.

3-(1, 2, 4-三氮唑)-4-(4-溴苯基)-2, 5-二氢-1, 5-苯并硫氮杂䓬(5d):黄色油状液体, 产率35%. ¹H NMR (CDCl₃, 500 MHz) δ: 7.86 (s, 1H), 7.46 (s, 1H), 7.41~6.86 (m, 8H), 6.10 (s, 1H), 3.82 (s, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ: 152.3, 144.9, 143.2, 139.0, 135.9, 133.7, 132.3, 129.7, 128.3, 125.8, 123.9, 122.1, 121.1, 114.5, 37.4; IR (KBr) ν: 3285, 1662 cm^－1; HRMS calcd for C₁₇H₁₄N₄SBr [M+H]⁺ 385.0117, found 385.0112.

3-(1, 2, 4-三氮唑)-4-(4-甲基苯基)-2, 5-二氢-1, 5-苯并硫氮杂䓬(5e):黄色油状液体, 产率40%. ¹H NMR (CDCl₃, 500 MHz) δ: 7.76 (s, 1H), 7.37 (s, 1H), 7.35~6.85 (m, 8H), 6.33 (s, 1H), 3.79 (s, 2H), 2.25 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ: 151.9, 144.9, 143.5, 139.9, 139.4, 134.1, 133.5, 129.5, 128.0, 125.6, 121.5, 121.1, 114.0, 60.3, 37.3; IR (KBr) ν: 3274, 1667 cm^－1; HRMS calcd for C₁₈H₁₇N₄S [M+H]⁺ 321.1168, found 321.1164.

3-(1, 2, 4-三氮唑)-4-(4-甲氧基苯基)-2, 5-二氢-1, 5-苯并硫氮杂䓬(5f):黄色油状液体, 产率37%. ¹H NMR (CDCl₃, 500 MHz) δ: 7.87 (s, 1H), 7.47 (s, 1H), 7.37~6.73 (m, 8H), 6.11 (s, 1H), 3.83 (s, 2H), 3.74 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ: 171.0, 160.3, 152.0, 145.0, 133.4, 129.5, 128.0, 121.5, 121.0, 114.2, 55.2, 37.2; IR (KBr) ν: 3396, 1667 cm^－1; HRMS calcd for C₁₈H₁₇N₄OS [M+1]⁺ 337.1118, found 337.1112.

3.2.4 3-(1, 2, 4-三氮唑)-4-芳基-2, 3, 4, 5-四氢-1, 5-苯并硫氮杂䓬6a~6f的合成

在50 mL三口瓶中, 分别加入4a~4f (0.33 mmol)、20.6 mg (0.33 mmol)氰基硼氢化钠、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, 乙醚重结晶得到化合物6a~6f.

5a~5f的还原步骤同上, 室温下反应4 h.

3-(1, 2, 4-三氮唑)-4-苯基-2, 3, 4, 5-四氢-1, 5-苯并硫氮杂䓬(6a):白色固体, 产率85%. m.p. 172~173 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 8.57 (s, 1H), 7.81 (s, 1H), 7.35~6.71 (m, 9H), 5.36 (s, 1H), 4.99 (dd, J_XA＝8.8 Hz, J_XB＝4.6 Hz, 1H), 3.92 (dd, J_AB＝14.6 Hz, J_AX＝8.8 Hz, 1H), 3.88 (s, 1H), 3.24 (dd, J_BA＝14.6 Hz, J_BX＝4.6 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 150.8, 148.4, 139.0, 132.0, 129.1, 128.4, 127.9, 125.8, 121.6, 120.5, 64.6, 63.0, 35.3; IR (KBr) ν: 3432 cm^－1; HRMS calcd for C₁₇H₁₇N₄S [M+H]⁺ 309.1168, found 309.1166.

3-(1, 2, 4-三氮唑)-4-(4-氟苯基)-2, 3, 4, 5-四氢-1, 5-苯并硫氮杂䓬(6b):白色固体, 产率82%. m.p. 186~188 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 8.62 (s, 1H), 7.83 (s, 1H), 7.36~6.72 (m, 8H), 5.34 (s, 1H), 4.97 (dd, J_XA＝8.8 Hz, J_XB＝4.4 Hz, 1H), 3.87 (dd, J_AB＝14.4 Hz, J_AX＝8.8 Hz, 1H), 3.78 (s, 1H), 3.25 (dd, J_BA＝14.4 Hz, J_BX＝4.4 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 162.4 (d, ¹J_CF＝246.8 Hz), 150.9, 148.2, 143.7, 132.1, 128.0, 127.6 (d, ³J_CF＝8.1 Hz), 121.8, 120.6, 116.1 (d, ²J_CF＝21.4 Hz), 64.5, 62.4, 35.3; IR (KBr) ν: 3435 cm^－1; HRMS calcd for C₁₇H₁₆N₄FS [M+H]⁺ 327.1074, found 327.1073.

3-(1, 2, 4-三氮唑)-4-(4-氯苯基)-2, 3, 4, 5-四氢-1, 5-苯并硫氮杂䓬(6c):白色固体, 产率82%. m.p. 207~209 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 8.61 (s, 1H), 7.83 (s, 1H), 7.35~6.72 (m, 8H), 5.34 (s, 1H), 4.97 (dd, J_XA＝8.4 Hz, J_XB＝4.6 Hz, 1H), 3.87 (dd, J_AB＝14.4 Hz, J_AX＝8.4 Hz, 1H), 3.79 (s, 1H), 3.24 (dd, J_BA＝14.4 Hz, J_BX＝4.6 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 150.9, 148.1, 143.7, 137.4, 134.4, 132.1, 129.3, 128.0, 127.2, 121.9, 120.7, 64.4, 62.4, 35.3; IR (KBr) ν: 3433 cm^－1; HRMS calcd for C₁₇H₁₆N₄ClS [M+H]⁺ 343.0779, found 343.0777.

3-(1, 2, 4-三氮唑)-4-(4-溴苯基)-2, 3, 4, 5-四氢-1, 5-苯并硫氮杂䓬(6d):白色固体, 产率83%. m.p. 210~212 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 8.61 (s, 1H), 7.84 (s, 1H), 7.38~6.72 (m, 8H), 5.33 (s, 1H), 4.97 (dd, J_XA＝8.4 Hz, J_XB＝4.8 Hz, 1H), 3.88 (dd, J_AB＝14.4 Hz, J_AX＝8.4 Hz, 1H), 3.78 (s, 1H), 3.25(dd, J_BA＝14.4 Hz, J_BX＝4.8 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 150.9, 148.1, 143.7, 137.9, 132.2, 132.1, 128.0, 127.5, 122.5, 121.9, 120.7, 64.3, 62.5, 35.3; IR (KBr) ν: 3433 cm^－1; HRMS calcd for C₁₇H₁₆N₄SBr [M+H]⁺ 387.0274, found 387.0273.

3-(1, 2, 4-三氮唑)-4-(4-甲基苯基)-2, 3, 4, 5-四氢-1, 5-苯并硫氮杂䓬(6e):白色固体, 产率80%. m.p. 184~186 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 8.58 (s, 1H), 7.82 (s, 1H), 7.34~6.69 (m, 8H), 5.31 (s, 1H), 4.96 (dd, J_XA＝8.6 Hz, J_XB＝4.6 Hz, 1H), 3.88 (dd, J_AB＝14.6 Hz, J_AX＝8.6 Hz, 1H), 3.84 (s, 1H), 3.23 (dd, J_BA＝14.6 Hz, J_BX＝4.6 Hz, 1H), 2.28 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 150.7, 148.6, 143.8, 138.2, 136.0, 132.0, 129.7, 127.9, 125.7, 121.5, 120.5, 64.6, 62.8, 35.3, 21.1; IR (KBr) ν: 3432 cm^－1; HRMS calcd for C₁₈H₁₉N₄S [M+H]⁺ 323.1325, found 323.1323.

3-(1, 2, 4-三氮唑)-4-(4-甲氧基苯基)-2, 3, 4, 5-四氢- 1, 5-苯并硫氮杂䓬(6f):白色固体, 产率79%. m.p. 161~162 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 8.59 (s, 1H), 7.84 (s, 1H), 7.34~6.69 (m, 8H), 5.30 (s, 1H), 4.94 (dd, J_XA＝8.6 Hz, J_XB＝4.6 Hz, 1H), 3.88 (dd, J_AB＝14.6 Hz, J_AX＝8.6 Hz, 1H), 3.79 (s, 1H), 3.75 (s, 3H), 3.23 (dd, J_BA＝14.6 Hz, J_BX＝4.6 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 159.4, 148.6, 132.0, 131.1, 127.9, 127.0, 121.5, 120.4, 114.4, 64.6, 62.4, 55.2, 35.3; IR (KBr) ν: 3432 cm^－1; HRMS calcd for C₁₈H₁₉N₄OS [M+H]⁺ 339.1274, found 339.1271.

3.3 体外抗菌活性

3.3.1 抑菌圈的测定

本实验采用酵母滤纸法^[25]对目标物进行抑菌活性的测定, 分别以氟康唑和盐酸环丙沙星作为抑真菌和细菌的对照药物, 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)、白色念珠菌(C. albicans)、金黄色葡萄球菌(S. aureus)和大肠杆菌(E. coli)的抑制作用.

将化合物4a~4f, 5a~5f, 6a~6f用二甲亚砜(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.

3.3.2 最小抑菌浓度(MIC₈₀)和最小杀菌浓度(MFC)的测定

将待测化合物用无菌液体培养基倍比稀释, 接入等体积的菌浓度为(2~3)×10³/mL CFU新生隐球菌菌悬液, 以不加任何试样的培养基并接入等体积的菌悬液为对照, 于37 ℃恒温培养36 h, 采用可见分光光度计在530 nm波长下测定光密度(OD)值.所测OD值下降80%时对应的最小试样浓度为MIC₈₀, 所测OD值与空白培养基OD值无显著差异时, 将对应的不同浓度试样处理的培养液涂平板, 没有菌落生长时的最小试样浓度即为MFC^[26].

辅助材料(Supporting Information) 中间体及目标化合物的核磁共振图谱.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 地尔硫䓬、喹硫平及氯噻平的结构

Figure 1 Structures of diltiazem, quetiapine and clotiapine

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图式 1 化合物的合成路线

Scheme 1 Synthetic route of compounds

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表 1 化合物4a~4f, 5a~5f和6a~6f的抑菌活性(抑菌圈直径/mm)^a^, ^b

Table 1. Antimicrobial activity of compounds 4a~4f, 5a~5f and 6a~6f (diameter of inhibition zone/mm)

Compd.	R	C. neoformans stand	C. neoformans clinical	C. albicans	S. aureus	E. coli
4a	H	29.30	28.37	25.93	17.00	15.57
4b	F	27.47	25.80	20.47	17.30	14.83
4c	Cl	21.10	20.30	15.20	13.17	11.63
4d	Br	17.50	17.33	15.20	12.10	10.03
4e	CH₃	25.63	25.30	22.67	14.17	12.63
4f	OCH₃	21.33	22.97	17.87	14.03	13.00
5a	H	23.43	18.63	20.03	16.53	14.97
5b	F	21.40	16.67	15.30	9.33	7.63
5c	Cl	26.43	26.60	12.93	11.13	10.17
5d	Br	21.93	23.10	10.00	8.67	8.93
5e	CH₃	18.33	17.33	15.43	8.67	8.73
5f	OCH₃	19.87	17.40	18.67	16.13	16.47
6a	H	6.00	6.00	6.00	6.00	6.00
6b	F	6.00	6.00	6.00	6.00	6.00
6c	Cl	23.67	23.66	6.00	6.00	6.00
6d	Br	20.80	20.51	6.00	6.00	6.00
6e	CH₃	6.00	6.00	6.00	6.00	6.00
6f	OCH₃	6.00	6.00	6.00	6.00	6.00
Fluconazol	—	22.40	22.40	20.20	—	—
Ciprofloxacin hydrochloride	—	—	—	—	21.60	21.60
^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 consider as no antibacterial activity.

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表 2 化合物4a, 4b, 4e和5c的MIC₈₀和MFC数据

Table 2. MIC₈₀ and MFC values of compounds 4a, 4b, 4e and 5c

Compd.	R	MIC₈₀/(µg•mL^－1)		MFC/(µg•mL^－1)
Compd.	R	ATCC34874	Clinical isolate	ATCC34874	Clinical isolate
4a	H	2.0	2.0	65.0	71.0
4b	F	2.0	2.0	72.0	74.0
4e	CH₃	3.0	3.0	58.0	58.0
5c	Cl	3.0	3.0	73.0	77.0
Fluconazol	—	2.0	3.0	＞128.0	＞128.0

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