喹诺酮类化合物的合成及其抗结核活性研究

【作者】 陈泠；

【导师】 陈国良；

【作者基本信息】 沈阳药科大学 ， 药物化学， 2006， 硕士

【摘要】 本论文总结了近年来结核病疫情现状，对喹诺酮类、硝基咪唑类、氨基糖苷类等十三类抗结核药物的研发与进展进行了详细的综述。喹诺酮类药物对结核杆菌有很好的抑制及杀灭作用，其中环丙沙星和左氧氟沙星用于耐多药结核病（MDR-TB）的治疗已取得良好疗效。它们能缩短结核病的疗程，价格低廉，毒副作用较小，并且与其他抗结核药物不产生交叉耐药性。理想的抗结核病喹诺酮类药物的抗菌谱应窄，最好仅对分枝杆菌有作用。本论文以环丙沙星和左氧氟沙星合成的关键中间体左氟酯为起始原料，分别合成它们母体结构七位哌嗪基4′位取代的烷基化、酰基化衍生物，以期获得具有高选择性抗结核活性的新化合物，共合成29个目标化合物，目标化合物均未见文献报道，经核磁共振氢谱和质谱确证结构。所有目标化合物进行了体外初步抗结核活性测试，采用微孔板美兰比色法（MABA）测定目标化合物对人型结核分枝杆菌H₃₇Rv的最小抑菌浓度（MIC）。结果表明，有七个目标化合物（C5、C6、C12、O4、O6、O9、O11）对H₃₇Rv菌株具有非常强的抑制作用，与设计思想一致，有进一步开发价值。对于有活性的化合物将进行其它抗菌活性的研究。更多还原

【Abstract】 A summary of tuberculosis（TB） situation of recent years and a detailed review of the research and development of 13 kinds of anti-TB drugs are presented in this thesis. The fluoroquinolones show pronounced activity against mycobacterium tuberculosis. The most interesting fluoroquinolones used currently in clinic are ciprofloxacin and levofloxacin. They are effective in the therapy of MDR-TB and can also shorten the period of treatment. They are inexpensive and have less side-effects. The ideal anti-TB drugs of fluoroquinolones should have little effect to other bacteria. In order to find new compounds with more powerful anti-mycobacterial activity and higher selectivity, in this thesis, ciprofloxacin and norlevofloxacin as the lead compounds, we designed and prepared 29 N-substituted ciprofloxacin and norlevofloxacin analogs which were not reported in literatures. Their structures were confirmed by ¹H-NMR and MS.The MICs to H₃₇Rv of all target compounds were tested by Microplate Alamar Blue Assay. According to the results, seven compounds C5、C6、C12、O4、O6、O9、O11 have strong Anti-mycobacterial activity, which is in accord with our designing thoughts. The activity tests to other bacteria of these seven compounds are under investigation.更多还原