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基于抗菌氟喹诺酮的作用靶拓扑异构酶与哺乳动物的相似性,为寻找由抗菌活性到抗肿瘤活性转化的有效修饰方法,用噁二唑杂环作为诺氟沙星(1)的羧基电子等排体得中间体,1-乙基-6-氟-7-(哌嗪-1-基)-3-(5-巯基-1,3,4-噁二唑-2-基)-喹啉-4(1H)-酮(3),化合物3与氯甲基噁二唑(4a～4e)进行S-醚化得双噁二唑甲硫醚(5a～5e),再进一步甲基化和季铵化得相应的N-甲基双噁二唑甲硫醚(6a～6e)和N,N-二甲基双噁二唑甲硫醚碘化物(7a～7e)。双噁二唑甲硫醚目标物的结构经元素分析、1H NMR、MS技术确证。采用MTT法评价了目标化合物对体外培养人肝癌细胞株Hep-3B生长的抑制活性。结果表明,15个目标化合物的抑制活性均显著高于对照化合物1的抑制活性,其季铵盐的IC50值低于25.0μmol/L,显示出潜在的抗癌活性。
Based on the similarity between the target topoisomerase and mammal in the antibacterial fluoroquinolones, in order to find an effective method for the transformation from antibacterial activity to antitumor activity, the oxadiazole heterocycle was used as the carboxyl group of norfloxacin (1) Isostere intermediates, 1-ethyl-6-fluoro-7- (piperazin- 1 -yl) -3- (5-mercapto- 1, 3,4-oxadiazol-2-yl) -quinoline S-etherification of compound 3 with chloromethyloxadiazole (4a-4e) gave dioxadiazolyl sulfide (5a-5e), which was further methylated and Quaternization gave the corresponding N-methylbisoxadiazole dimethylsulfide (6a-6e) and N, N-dimethylbisoxadiazole dimethylsulfide iodide (7a-7e). The structure of the target compound of dioxadiazole methyl sulfide was confirmed by elemental analysis, 1H NMR and MS techniques. The inhibitory activity of the target compound on the growth of human hepatocellular carcinoma cell line Hep-3B in vitro was evaluated by MTT assay. The results showed that the inhibitory activity of 15 target compounds were significantly higher than the inhibitory activity of the control compound 1, the quaternary ammonium IC50 value of less than 25.0μmol / L, showing a potential anti-cancer activity.