有机化学 ›› 2014, Vol. 34 ›› Issue (9): 1773-1779.DOI: 10.6023/cjoc201404042 上一篇    下一篇

研究论文

3-芳基-2(5H)-呋喃酮-氟喹诺酮杂合体多靶点抗菌化合物的设计、合成及其作用机理研究(约稿)

王旭东, 魏伟, 邓瑞成, 周沙沙, 张蕾, 林肖依, 肖竹平   

  1. 吉首大学化学化工学院, 吉首 416000
  • 收稿日期:2014-04-26 修回日期:2014-06-04 出版日期:2014-09-25 发布日期:2014-07-01
  • 通讯作者: 肖竹平 E-mail:xiaozhuping2005@163.com
  • 基金资助:

    国家自然科学基金(No. 21262013)、湖南省自然科学基金(No. 13JJ2030)和湖南省高校科技创新团队支持计划资助项目.

3-Arylfuran-2(5H)-one-fluoroquinolone Hybrids as Multi-target Antibacterial Agents: Design, Synthesis and Its Mechanistic Implication

Wang Xudong, Wei Wei, Deng Ruicheng, Zhou Shasha, Zhang Lei, Lin Xiaoyi, Xiao Zhuping   

  1. College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000
  • Received:2014-04-26 Revised:2014-06-04 Online:2014-09-25 Published:2014-07-01
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 21262013), the Hunan Provincial Natural Science Foundation (No. 13JJ2030), and the Science and Technology Innovative Research Team in Higher Educational Instituions of Hunan Province.

借助杂合体药物和多靶点药物的设计方法,将含有3-芳基-2(5H)-呋喃酮结构单元的酪氨酰t-RNA合成酶抑制剂与氟喹诺酮(DNA促旋酶抑制剂)相融合,设计合成了7个结构全新的3-芳基-2(5H)-呋喃酮-氟喹诺酮杂合体化合物. 体外抗菌活性筛选发现,大多数化合物对革兰氏阳性菌、革兰氏阴性菌以及真菌均具有较好抑制作用. 酶活性评价和分子模拟研究表明,该类化合物是通过干扰蛋白质合成和DNA复制来发挥抑菌作用的双重抑制剂. 这些结果充分说明,3-芳基-2(5H)-呋喃酮-氟喹诺酮杂合体化合物作为抗菌化合物有进一步研究的价值.

关键词: 2(5H)-呋喃酮, 氟喹诺酮, 杂合体, 多靶点, 抑制剂

Based on the multi-target drug design and hybrid strategy for drug research and development, seven new 3-arylfuran-2(5H)-one-fluoroquinolone hybrids have been designed and synthesized, in which the 3-aryl-4-(2-morpholino- ethoxy)furan-2(5H)-one (targeting tyrosyl-tRNA synthetase, TyrRS) and fluoroquinolone (targeting DNA gyrase) were merged. In the antibacterial assay, most of the tested compounds displayed a broad spectrum of activity against microorganisms including Gram-negative bacteria, Gram-positive bacteria and fungi. Furthermore, the enzyme assay and molecular docking revealed that 3-arylfuran-2(5H)-one-fluoroquinolone is a potent antibacterial agent by disturbing the processes of bacterial DNA replication and protein synthesis. These excellent results strongly suggest that 3-arylfuran-2(5H)-one-fluoroquinolone hybrid deserves to further research as a novel antibiotic.

Key words: 3-arylfuran-2(5H)-one, fluoroquinolone, hybrid, multi-target, inhibitor