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化学学报
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化学学报 ›› 2008, Vol. 66 ›› Issue (24): 2725-2729. 上一篇    下一篇

研究论文

新型α1受体拮抗剂先导化合物的寻找(I): 5-氯-2-(4-(芳氧烷基)哌嗪-1-基)苯并噁唑类化合物的设计、合成及生物活性研究

李嘉宾a 江振洲b 王 涛b 刘明明a
夏 俊c 吴 斌d 夏 霖*,e

  

  1. (a中国药科大学 无机化学教研室 南京 210009)
    (b中国药科大学 新药筛选中心 南京 210009)
    (c中国药科大学 新药研究中心 南京 210009)
    (d南京医科大学 药物化学教研室 南京 210029)
    (e中国药科大学 药物化学教研室 南京 210009)

  • 投稿日期:2008-09-23 修回日期:2008-11-04 发布日期:2008-12-28
  • 通讯作者: 夏霖

Searching for the Novel Lead Compounds of α1-AR Antagonists (Part I): Design, Synthesis and Bioassay of 5-Chloro-2-[4-(aryloxyalkyl)piperazin-1-yl] benzo[d]oxazole Compounds

LI, Jia-Bin a JIANG, Zhen-Zhou b WANG, Tao b LIU, Ming-Ming a
XIA, Jun c WU, Bin d XIA, Lin *,e
  

  1. (a Department of Inorganic Chemistry, China Pharmaceutical University, Nanjing 210009)
    (b National Drug Screening Center, China Pharmaceutical University, Nanjing 210009)
    (c New Drug Research Center, China Pharmaceutical University, Nanjing 210009)
    (d Department of Medicinal Chemistry, Nanjing Medical Univeristy, Nanjing 210029)
    (e Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009)
  • Received:2008-09-23 Revised:2008-11-04 Published:2008-12-28
  • Contact: XIA, Lin

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1180

被引次数

10

为寻找用于治疗良性前列腺增生的新型α1受体拮抗剂, 以本研究组发现的2-[(4-(2-(2-氯苯氧基)乙基)哌嗪-1-基)甲基]-5-甲基苯并噁唑(wb5c)为先导化合物, 结合已构建的α1-AR拮抗剂药效团模型, 通过骨架改造, 设计出以苯并噁唑-2-基哌嗪为母核的目标物, 然后以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、取代等反应共合成11个新目标化合物, 结构经ESI-MS, 1H NMR, IR及HRMS确证. 初步药理活性实验表明, 目标物具有中等强度α1受体拮抗活性, 符合我们提出的三元素药效团模型. 5-氯-2-[4-(芳氧烷基)哌嗪-1-基]类化合物是一类新的具有潜在开发价值的α1受体拮抗剂.

关键词: 良性前列腺增生, α1受体, 拮抗剂, 药效团, 苯并噁唑, 哌嗪

To search for the new α1-adrenoceptor antagonists, 11 target compounds bearing a 2-(piperazin-1-yl) benzo[d]oxazole scaffold were designed from our lead compound 2-[(4-(2-(2-chloropheno-
xy)-ethyl)-piperazin-1-yl)methyl]-5-methylbenzo[d]oxazole (wb5c) and synthesized from 5-chloro-2- aminophenol and substituted phenols via condensation, chloration, amination, Williamson ether synthesis and substitution etc. All the target compounds were identified by ESI-MS, IR, 1H NMR and HRMS. Functional bioassay showed that they had moderate antagonistic activities against α1-AR, which verified our three-element pharmacophore model. In conclusion, 5-chloro-2-(4-(aryloxyalkyl)piperazin-1-yl)benzo- [d]oxazole compounds were novel candidates as potential α1-AR antagonist.

Key words: benign prostatic hyperplasia, α1-adrenoceptor, antagonist, pharmacore, benzoxazole, piperazine