高等学校化学学报 ›› 2015, Vol. 36 ›› Issue (4): 687-697.doi: 10.7503/cjcu20140875

• 有机化学 • 上一篇    下一篇

4-氟苯基-2,3-二氢-1,5-苯并[b]硫氮杂䓬类化合物的合成、结构和抑真菌活性

张静1, 穆博帅1, 吴萌2, 边艳青2(), 李媛1()   

  1. 1. 河北师范大学化学与材料科学学院
    2. 生命科学学院, 石家庄 050024
  • 收稿日期:2014-09-26 出版日期:2015-04-10 发布日期:2015-03-19
  • 作者简介:联系人简介: 边艳青, 女, 博士, 副教授, 主要从事微生物及免疫学研究. E-mail: bianyanqing151@sohu.com. 李 媛, 女, 教授, 主要从事有机合成研究. E-mail: liyuanhbsd@163.com
  • 基金资助:
    国家自然科学基金(批准号: 20972040)资助

Synthesis, Antifungal Activity and Structure-activity Relationship of -Fluorophenyl-2,3-dihydro-1,5-benzothiazepines Derivatives

ZHANG Jing1, MU Boshuai1, WU Meng2, BIAN Yanqing2,*(), LI Yuan1,*()   

  1. 1.College of Chemistry and Material Science
    2. College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, China
  • Received:2014-09-26 Online:2015-04-10 Published:2015-03-19
  • Contact: BIAN Yanqing,LI Yuan E-mail:bianyanqing151@sohu.com;liyuanhbsd@163.com
  • Supported by:
    † Supported by the National Natural Science Foundation of China(No.20972040)

摘要:

合成了26个4-氟苯基取代的1,5-苯并硫氮杂?类化合物2a~2z, 其结构经核磁共振波谱、 红外光谱和高分辨质谱确证. 采用抑菌圈法测试了其对白色念珠菌和新生隐球菌的抑菌活性, 结果表明, 4-(2,3-二氟苯基)/(2,5-二氟苯基)/(3,4-二氟苯基)-2,3-二氢-1,5-苯并[b]硫氮杂?(2a~2f)对新生隐球菌有较强的抑制作用, 但杂?2a~2z对白色念珠菌均无活性. 进一步考察了高活性杂?2a~2f对新生隐球菌的最小抑菌浓度(MIC, MIC80)和最小杀菌浓度(MFC), 发现其MIC和MFC远低于对照药氟康唑. 在此基础上, 对杂?2a~2f进行了初步构效关系研究, 并合成了4个系列21个杂?衍生物3a~3f, 4a~4f, 5a~5f和6a~6c. 通过考察其对新生隐球菌的抑菌效果, 证明了杂?2a~2f分子中的硫原子、 碳氮双键结构单元以及2位的甲氧/乙氧羰基是该类化合物抑真菌的必需基团.

关键词: 1,5-苯并硫氮杂?, 抑真菌活性, 构效关系

Abstract:

Twenty-six 4-fluoropheny-2,3-dihydro-l,5-benzothiazepine derivatives 2a—2z were synthesized and characterized by 1H NMR, 13C NMR, IR and high resolution mass spectrum(HRMS). The antifungal activities of those compounds were screened using the disk diffusion method against C. albicans and C. neoformans. The results showed that benzothiazepines 2a—2f had high antifungal activities against C. neoformans, while all of the benzothiazepines 2a—2z were almost inactive against C. albicans. Furthermore, the 1,5-benzothiazepines 2a—2f, which had high antifungal activities, were subjected to further pharmacological evaluation, including minimum inhibitory concentration(MIC, MIC80) and minimum fungicidal concentration(MFC) against C. neoformans. The results revealed that the MIC and MFC values for the above compounds were much lower than those of fluconazole. In order to study the structural features responsible for the antifungal activity of compounds 2a—2f, four series of analogues 3a—3f, 4a—4f, 5a—5f and 6a—6c were synthesized and tested for their antifungal activities against C. neoformans. The results suggested that the sulfur atoms, C=N structure on the seven-membered ring and the methoxycarbonyl/ethoxycarbonyl group at the 2 position are essential for antifungal activity.

Key words: 1,5-Benzothiazepine, Antifungal activity, Structure-activity relationship

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