高等学校化学学报 ›› 2014, Vol. 35 ›› Issue (12): 2574-2583.doi: 10.7503/cjcu20140353

• 有机化学 • 上一篇    下一篇

2-甲氧/乙氧羰基-4-氟苯基-1,5-苯并硫氮杂䓬的合成、抑真菌活性及构效关系

范世丽1, 张博1, 高丽叶1, 王兰芝1, 边艳青2(), 李媛1()   

  1. 1. 河北师范大学 化学与材料科学学院, 石家庄 050024
    2. 河北师范大学 生命科学学院, 石家庄 050024
  • 收稿日期:2014-04-14 出版日期:2014-12-10 发布日期:2014-11-29
  • 作者简介:联系人简介: 李 媛, 女, 教授, 主要从事有机合成研究. E-mail:liyuanhbsd@163.com; 边艳青, 女, 博士, 副教授, 主要从事微生物及免疫学研究. E-mail:353534578@qq.com
  • 基金资助:
    国家自然科学基金(批准号: 20972040, 21276064)资助

Synthesis, Antifungal Activity and Structure-activity Relationship of 2-Methoxycarbonyl/ethoxycarbonyl-4-fluorophenyl-1,5-benzothiazepines

FAN Shili1, ZHANG Bo1, GAO Liye1, WANG Lanzhi1, BIAN Yanqing2,*(), LI Yuan1,*()   

  1. 1. College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang 050024, China
    2. College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, China
  • Received:2014-04-14 Online:2014-12-10 Published:2014-11-29
  • Contact: BIAN Yanqing,LI Yuan E-mail:353534578@qq.com;liyuanhbsd@163.com
  • Supported by:
    † Supported by the National Natural Science Foundation of China(Nos.20972040, 21276064)

摘要:

以高活性的2-甲氧/乙氧羰基-4-(4-氟苯基)-1,5-苯并硫氮杂?A和B为模型化合物, 设计合成了11个含氟杂?衍生物3a~3k, 考察了它们对白色念珠菌和新生隐球菌的抑菌活性. 研究结果表明, 2-甲氧/乙氧羰基-4-(2-氟苯基)/(3-氟苯基)/(2,4-二氟苯基)-1,5-苯并硫氮杂?3a, 3b, 3d~3f对新生隐球菌有很强的抑菌活性, 3c的活性中等, 而7位氯代杂?3g~3k基本无活性; 上述杂?对白色念珠菌均无活性. 在此基础上, 进一步测试了高活性杂?3a, 3b, 3d~3f对新生隐球菌的抑菌浓度梯度、 最小抑菌浓度(MIC)和最小杀菌浓度(MFC), 发现其MIC和MFC均远低于对照药氟康唑. 为了考察杂?3a~3f的药效基团, 又设计合成了4类杂?衍生物4a~4f, 5a~5f, 6a~6f和7a~7c, 通过对其抑菌活性的评价, 发现分子中2-甲氧/乙氧羰基和亚胺官能团对杂?3a~3f的抑真菌(新生隐球菌)活性起关键作用, 硫原子被氧原子或氮原子代替后原杂?的活性降低.

关键词: 1,5-苯并硫氮杂?, 抑菌活性, 构效关系

Abstract:

Using A and B as the prototypical structure, eleven 1,5-benzothiazepine derivatives 3a—3k were synthesized and evaluated for their antifungal activity against C. albicans and C. neoformans via the disk diffusion method. The results showed that benzothiazepines 3a, 3b and 3d—3f had good antifungal activity against C. neoformans, compound 3c had moderate activity, and 7-chloro-substituted analogues 3g—3k were weakly active or inactive. In addition, all of the benzothiazepines 3a—3k were almost inactive against C. albicans. Furthermore, compounds 3a, 3b and 3d—3f, which had good antifungal activities, were subjected to further pharmacological evaluation, including determining the dose dependence of the antifungal activity, minimum inhibitory concentration(MIC) and minimum fungicidal concentration(MFC) against C. neoformans. The results showed that the MIC and MFC values for above compounds were much lower than those of fluconazole. In order to examine the structural features responsible for the antifungal activity of compounds 3a—3f, four series of 1,5-benzothiazepine derivatives 4a—4f, 5a—5f, 6a—6f and 7a—7c were synthesized and screened for their antifungal activity. The results demonstrated that the methoxycarbonyl/ethoxycarbonyl group at the 2 position and imine moiety on the seven-membered ring of benzothiazepines 3a—3f was critical to their biological activity. The results also indicated that replacement of sulfur atom in the molecules with nitrogen or oxygen atom led to decrease in activity of this series of compounds.

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

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