高等学校化学学报 ›› 2009, Vol. 30 ›› Issue (5): 903.

• 研究论文 • 上一篇    下一篇

新型α1受体拮抗剂先导化合物的寻找: 2-[4-(芳氧烷基)哌嗪-1-基]苯并噁唑的合成、生物活性及3D-QSAR研究

李嘉宾1, 刘海春1, 张立4, 王涛3, 江振洲3, 夏霖2   

    1. 中国药科大学无机化学教研室,
    2. 药物化学教研室,
    3. 新药筛选中心, 南京 210009;
    4. 中国科学院上海有机化学研究所上海质谱中心, 上海 200032
  • 收稿日期:2008-11-18 出版日期:2009-05-10 发布日期:2009-05-10
  • 通讯作者: 夏霖, 女, 教授, 博士生导师, 主要从事药物分子设计、合成及生物活性研究, E-mail: phenopro@cpu.edu.cn
  • 基金资助:

    国家“八六三”计划(批准号: 2002AA2Z3118)资助.

Searching for Novel Lead Compounds of α1-AR Antagonists: Synthesis, Bioassays and 3D-QSAR of 2-[4-(Aryloxyalkyl)-piperazin-1-yl]benzo[d]oxazole Compounds

LI Jia-Bin1, LIU Hai-Chun1, ZHANG Li4, WANG Tao3, JIANG Zhen-Zhou3, XIA Lin2*   

    1. Department of Inorganic Chemistry,
    2. Department of Medicinal Chemistry,
    3. New Drug Screening Center, China Pharmaceutical University, Nanjing 210009, China;
    4. Shanghai Mass Spectrometry Center, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China
  • Received:2008-11-18 Online:2009-05-10 Published:2009-05-10
  • Contact: XIA Lin, E-mail: phenopro@cpu.edu.cn

摘要:

为寻找用于治疗良性前列腺增生的新型α1受体拮抗剂, 以2-({4-[2-(2-氯苯氧基)乙基]哌嗪-1-基}甲基)-5-甲基苯并噁唑(wb5c)为先导物, 以5-氯-2-氨基酚和取代苯酚为原料, 经缩合、卤代、氨化、Williamson醚合成、取代等反应, 设计合成了8个新化合物, 其结构经ESI-MS, 1H NMR, IR及HRMS确证. 大鼠肛尾肌收缩功能实验表明, 目标化合物具有中等强度α1受体拮抗活性. 结合前期工作, 以18个2-[4-(芳氧烷基)哌嗪-1-基]苯并噁唑类化合物及其生物活性为样本, 运用Sybyl软件建立了该类化合物α1-AR拮抗活性的CoMFA模型, q2=0.430, r2=0.907, 立体场与静电场的贡献分别为46.5%和53.5%, 此模型为进一步结构优化提供了有益信息.

关键词: 良性前列腺增生, α1受体, 拮抗剂, 苯并噁唑, 哌嗪, 比较分子力场分析

Abstract:

Benign prostatic hyperplasia(BPH) is a pathological disorder in the aged men that causes voiding difficulties and thus impacts the quality of life. α1-AR antagonists are clinically used for the treatment of BPH. Aimed at searching for the novel α1-adrenoceptor antagonists, eight target compounds bearing 2-(piperazin-1-yl)benzo[d]oxazole scaffold were designed from our lead compound wb5c and synthesized from 5-chloro-2-aminophenol and substituted phenols via condensation, chloration and amination, Williamson ether synthesis and substitution etc.. All target compounds were identified by ESI-MS, IR, 1H NMR and HRMS. Functional bioassays showed that they had moderate antagonistic activities against α1-AR. The CoMFA model was constructed for 2-(piperazin-1-yl)benzo[d]oxazole derivertives via SYBYL software package, q2=0.430, r2=0.907, fractions of steric and electrostatic fields were 0.465 and 0.535, respectively. 3D-QSAR analysis leads to insight into further structural optimization.

Key words: Benign prostatic hyperplasia(BPH), α1-Adrenoceptor, Antagonists, Benzoxazole, Piperazine, CoMFA model

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