有机化学 ›› 2017, Vol. 37 ›› Issue (9): 2385-2391.DOI: 10.6023/cjoc201701049 上一篇    下一篇

研究论文

新型八氢吡咯[3,2-c]吡啶衍生物作为趋化因子受体(CCR5)抑制剂的设计、合成及生物活性研究

王雨捷a, Upul Halambagec, 曾程初a, 胡利明a,b   

  1. a 北京工业大学生命科学与生物工程学院 北京 100124;
    b 北京工业大学环境与病毒肿瘤学北京重点实验室 北京 100124;
    c Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center Nashville 37232
  • 收稿日期:2017-02-13 修回日期:2017-04-03 出版日期:2017-09-25 发布日期:2017-05-02
  • 通讯作者: 胡利明 E-mail:huliming@bjut.edu.cn
  • 基金资助:

    国家自然科学基金(No.21272020)、环境与病毒肿瘤学北京市重点实验室资助项目.

Design, Synthesis, and Biological Activity of Novel Octahydro-1Hpyrrolo[3,2-c]pyridine Derivatives as C-C Chemokine Receptor Type 5 (CCR5) Antagonists

Wang Yujiea, Halambage Upulc, Zeng Chengchua, Hu Liminga,b   

  1. a College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124;
    b Beijing Key Laboratory of Environmental and Viral Oncology, Beijing University of Technology, Beijing 100124;
    c Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville 27232
  • Received:2017-02-13 Revised:2017-04-03 Online:2017-09-25 Published:2017-05-02
  • Contact: 10.6023/cjoc201701049 E-mail:huliming@bjut.edu.cn

设计并合成一系列新型八氢吡咯[3,2-c]吡啶衍生物作为趋化因子受体(CCR5)抑制剂,并测试其抗人免疫缺陷病毒(HIV-1)生物活性.大多数化合物显示了抗HIV-1活性,其中,八氢吡咯[3,2-c]吡啶衍生物19c活性最好(IC50<1 μmol·L-1).但在研究其药物作用机理时发现,该化合物除作用于CCR5外,还可作用于其他抗HIV-1靶标.另外,利用计算机模拟、分子对接方法,对该系列化合物进行了初步的构效关系讨论.

关键词: HIV-1, CCR5抑制剂, 哌啶衍生物, 构效关系

A series of novel octahydro-1H-pyrrolo[3,2-c]pyridine derivatives were designed and synthesized as C-C chemokine receptor type 5 (CCR5) antagonists, and their biological activity of anti-human immunodeficiency virus type 1 (HIV-1) is evaluated. A majority of these compounds showed anti-HIV-1 activities. Octahydro-1H-pyrrolo[3,2-c]pyridine derivative 19c exhibited potency against HIV-1 replication less than 1 μmol·L-1. Function assay was employed and the result showed that there were other drug targets for HIV-1 inhibition besides CCR5. In addition, the preliminary structure-activity relationship (SAR) of these compounds was rationalized by docking studies.

Key words: HIV-1, CCR5 antagonists, piperidine derivatives, structure-activity relationships