水溶性稠杂环均三唑并噻二唑体系的合成及生物活性(II): 环丙氟喹诺酮哌嗪衍生物

为发现3-位稠杂环取代喹诺酮衍生物新的生物活性, 以环丙氟氯喹诺酮羧酸(1)为起始原料, 经3步反应得到3-(4-氨基-5-巯基-均-三唑)氟氯喹酮(4). 在常温加热和微波辐射条件下, 4与异烟酸缩环合反应得到中间体3-6-吡啶-3- 均三唑3,4-b]1,3,4]噻二唑]氟氯喹诺酮(5). 喹诺酮环上的氯原子与取代哌嗪在聚乙二醇和无机碱催化作用下发生选择性亲核取代反应, 形成相应的3-(6-吡啶-3-均三唑3,4-b]1,3,4]噻二唑)氟喹诺酮哌嗪游离碱, 与盐酸反应得相应水溶性盐酸盐6. 同时也发现, 用1的酯化物却不能得到中间体2, 而仅得到环丙氟氯吡唑并喹啉酮(3). 新化合物的结构经元素分析和光谱数据表征, 用MTT和二倍试管稀释方法评价了它们体外对CHO, HL60和L1210 3种癌细胞株及S. aureus和E.coli 2种菌株的抑制活性. 结果表明, 在合成的9个新化合物中, 化合物3和 6具有潜在的体外抑制癌细胞生长活性, 其中6的IC50均在50 mmol/L以下, 尤其是化合物6a和6d对L1210的IC50值达到8.0×10－6 mol/L以下, 显示良好的选择性和体外活性; 目标化合物体外抑菌试验有意义的发现, 虽然抑菌活性不及对照环丙沙性, 但对革兰阳性菌活性显著高于对阴性菌的活性, 这与喹诺酮药物的抗菌活性相反. 以上结果表明, 氟喹诺酮类抗菌剂的3位稠杂环取代衍生物作为新结构抗肿瘤或抗菌先导物具有进一步研究和开发的价值.

Synthesis and Bioactivity of Water-soluble Fused s-Triazolothiadiazole Systems(Ⅱ):Fluoroquinolone Piperazine Derivatives

To discover the novel bioactivities of quinolone derivatives substituted by a fused heterocyclic ring at the 3-position, the key intermediate of 3-(1-amino-5-mercapto-1H-1,3,4-triazol-2-yl)-7-chloro-1- cyclopropyl-6-1,4-dihydroquinolin-4-one (4) was synthesized via a three-step procedure starting from 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1). Compound 4 was subjected to cyclocondensation with isonicotinic acid under microwave irradiation (MWI) to yield the fused system of 7-chloro-1-cyclopropyl-6-fluoro-3-2-(pyridin-4-yl)-1,3,4]-triazolo2,1-b]1,3,4]thiadiazol-4-yl]- 1,4-hydroquinolin-4-one (5) in a higher yield than that of the classical thermal heating. However, it was surprisingly to find that condensation of the corresponding esters of 1 with hydrazine hydrate produced an unexpected product of pyrazoloquinolone 3 instead of its hydrazide 2. The following selective nucleophilic substitution of halogens at the quinolone framework of compound 5 with substituted piperazine under catalyst of PEG-600 and inorganic base gave the corresponding fluorinated free bases 6 successfully, which were subsequently transformed to the corresponding 6•HCl salts by the treatment with hydrochloride. The structures of new compounds synthesized were characterized by elemental analysis and spectral data, and their in vitro antibacterial and anticancer activities against the three cancer cell lines of CHO, HL60 and L1210 along with the two microorganisms of S. aureus and E.coli were also evaluated, respectively. The bioactive assay revealed that compounds 3 and 6, especially 6a and 6d exhibited a significant antitumor activity against HL60 with the IC50 values from 50.0 to 8.0 μmol/L. More interestingly, although the title compounds 6 showed a poorer inhibitory activity than ciprofloxacin, they had a stronger inhibitory activity against gram-negative E.coli than that of gram-positive S. aureus. Thus, the fused heterocycle-based substituted quinolones are valuable for further study.