氟喹诺酮C3均三唑噁二唑甲硫醚衍生物的合成及抗肿瘤活性

Synthesis and Antitumor Evaluation of Fluoroquinolon C3 s-Triazole Oxadiazole Methylsulfide Derivatives of Ofloxacin

目的寻找抗菌氟喹诺酮转化为抗肿瘤活性的C3羧基有效生物电子等排体。方法均三唑杂环作为抗菌氟喹诺酮氧氟沙星(1)C3羧基的等排体,用噁二唑作为修饰杂环,设计合成了C3双异杂环均三唑噁二唑甲硫醚目标化合物,6-氟-7-(4-甲基哌嗪-1-基)1,8-(2,1-氧丙基)-3-[5-(5-芳基-[1,3,4]-噁二唑-2-甲硫基)-4H-[1,2,4]-三唑-3-基]-喹啉-4(1H)-酮(6a^6j),用噻唑蓝(MTT)方法评价其体外抗肿瘤活性。结果合成了10个新双异杂环硫醚目标化合物,体外抗肿瘤活性显著高于母体化合物氧氟沙星的活性。结论均三唑杂环可作为C-3羧基的有效等排体。

ABJECTIVE To explore an efficient heterocyclic bioisostere as the C3 carhoxylic group of antibacterial fluoroquinolo- nes for further development of antitumor fluoroquinolones. METHODS Using the s-triazole ring as an isosteric replacement of the C3 carboxylic group with another different heteroeyelic ring, oxadiazole, as a modified group, new his-（ different azole）methylsulfide deriva- tives, 6-fluoro-7- （4-methyl-piperazin- 1 -yl） -1,8- （ 2,1 -oxpropyl ） -5- [ 5- （ aryl- [ 1,3,4 ] -oxadiazol- 2-methylsulfanyl ） -4H- [ 1,2,4 ] -tri- azol-3yl] -quinolin-4 （IH） -ones （ 6a - 6j ） , were designed from ofloxacin （ 1 ）. The in vitro antitumor activity of 6a - 6j against three cancer cell lines was evaluated by MTT assay. RESULTS Ten title compounds （6a -6j）were synthesized and their structures were characterized by spectral data. They exhibited significantly higher in vitro antitumor potency than the parent compound ofloxacin. CONCLUSION The heterocyclic ring,s-triazole, could be used as an efficient isostere of the C-3 earboxylie group for further develop- ment of antitumor fluoroquinolone candidates.