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化学学报
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化学学报 ›› 2008, Vol. 66 ›› Issue (8): 980-984. 上一篇    下一篇

研究论文

水溶性稠杂环均三唑并噻二唑体系的合成及生物活性(I): 哌嗪取代衍生物

胡国强*,1，侯莉莉1，谢松强1，杜钢军1，黄文龙2，张惠斌2   

  1. (1河南大学药物研究所 开封 475001)
    (2中国药科大学新药中心 南京 210009)
  • 投稿日期:2007-07-18 修回日期:2007-11-29 发布日期:2008-04-28
  • 通讯作者: 胡国强

Synthesis and Bioactivity of Water-soluble Fused s-Triazolothiadiazole Systems (I): Functionalized Piperazine Derivatives

HU Guo-Qiang*,1 HOU Li-Li1 XIE Song-Qiang2 DU Gang-Jun1 HUANG Wen-Long2 ZHANG Hui-Bin2   

  1. (1 Institute of Pharmacy, Henan University, Kaifeng 475001)
    (2 Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009)
  • Received:2007-07-18 Revised:2007-11-29 Published:2008-04-28
  • Contact: HU Guo-Qiang

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4-氨基-5-吡啶-4-基-均三唑硫醇(1)在复合催化剂DMAP和TBAB作用下与对卤代苯甲酸经环缩合反应以高收率得到中间体6-(5-氯-3-甲基-1-取代苯基-1H-吡唑-4-基)-3-吡啶-3-基-均三唑并[3,4-b][1,3,4]噻二唑(2a～2c), 接着苯环卤原子与取代哌嗪在聚乙二醇催化作用下发生亲核取代反应得到相应的哌嗪游离碱(3a～3c). 其中, 单取代哌嗪游离碱3a与含功能基的卤代物缩合得到功能基取代的哌嗪衍生物(4a～4g). 这些产生的游离碱与盐酸反应得到相应的水溶性盐酸盐. 所合成新化合物的结构经元素分析和光谱数据表征, 并评价了它们的体外抗菌活性及构效关系.

关键词: 均三唑, 均三唑并噻二唑, 哌嗪, 抗菌活性, 构效关系

6-p-Halophenyl-3-pyrid-4-yl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (2a～2c) were synthesized by a composite catalyst of phase transfer catalysts tetrabutylammonium bromide (TBAB) and (4-dimethylaminopyridine (DMAP) via cyclo-condensation of 4-amino-5-pyridin-4-yl-s-triazole-3-thiol (1) with para halogenated benzoic acids in the presence of POCl3 in high yields, and the following nucleophilic substitution of halogen at phenyl ring with substituted piperazine under catalysis of PEG-600 gave the corresponding free bases 3a～3c successfully. Among them, mono substituted piperazine free base 3a was reacted with functionalized halides to give corresponding bis-substituted piperazine derivatives 6-[4-(4-substituted piperazin-1-yl)phenyl]-3-pyrid-4-yl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 4a～4g. These yielded piperazine free bases were treated with hydrochloride to the respective HCl salts. The structures of new compounds synthesized were characterized by elemental analysis and spectral data, and their in vitro antibacterial activity and structure-activity relationships were also evaluated.

Key words: s-triazole, s-triazolothiadiazole, piperazine, antibacterial activity, structure-activity relationship (SAR)