6-氟-4-喹诺酮类杂合分子的合成及体外抗菌活性研究

Synthesis and antibacterial activity of hybrid drug molecules of 6-fluoro-4-quinolone derivatives

目的筛选新型抗耐药的具有抗菌活性的6-氟-4-喹诺酮类杂合化合物。方法以诺氟沙星和6-氟-4-喹诺酮-3-羧酸乙酯为主体,与异烟肼、妥曲珠利、青蒿素衍生物和1,2,4-三唑衍生物等结构单元进行杂合,设计了一系列新杂合分子,通过酰胺缩合、烷基化、Mannich反应以及Schiff反应等得到目标化合物。采用测定最小抑菌浓度法,测定目标化合物对革兰阳性菌-耐甲氧西林金黄色葡萄球菌(MRSA)和革兰阴性菌-铜绿假单胞菌(Pae)的体外抗菌活性。结果与结论合成了11个全新的6-氟-4-喹诺酮类杂合分子,所有目标化合物的结构经ESI-MS、1H-NMR谱确证。体外抗菌活性测试结果表明绝大部分目标化合物具有一定的抗菌活性,其中化合物D对Pae表现出更好的抗菌活性(MIC值为1.0μg·mL^(-1),优于阳性对照药诺氟沙星3.9μg·mL^(-1));化合物J对MRSA表现出更好的抗菌活性(MIC值为4.2μg·mL^(-1),优于阳性对照药诺氟沙星7.8μg·mL^(-1))。结合修饰过的分子结构和反应位点,总结其构效关系,为该类新型杂合化合物研究提供参考。

Due to the over-use of antibiotics,more and more serious drug-resistant bacterium have emerged.In order to dig out more efficient and anti-drug resistance hybrid molecules with antibacterial activity,eleven novel anti-drug resistance 6-fluoro-4-quinolone derivatives hybrid compounds were designed and synthesized.These compounds were hybrided by the structural units of 6-fluoro-4-quinolone-3-carboxylate,norfloxacin,isoniazid,isatin,toltrazuril,artemisinin derivatives and 1,2,4-triazole derivatives.They were prepared by amide coupling,alkylation,Mannich and Schiff reaction started from norfloxacin and 6-fluoro-4-quinolone-3-carboxylate.The structures of these compounds were confirmed by ESI-MS and ^(1)H-NMR.The antibacterial activities in vitro of the target compounds were determined by MIC test.And a part of these compounds showed better antibacterial activities against methicillin-resistant Staphylococcus aureusm(MRSA)and Pseudomonas aeruginosa(Pae)compared with the standard sample of norfloxacin,especially for compounds D and J.The structure activity relationships of the target compounds and the key reactive position on C-7 and N-1 of 6-fluoro-4-quinolone derivatives were summarized,which can provide references for further research.