1-环丙基-6-氟-7-(芳甲叉肼基)-喹诺酮羧酸的合成及抗菌抗肿瘤活性

Synthesis, antibacterial and antitumor activities of 1-cycloproyl-6-fluoro-7-( hydrazone)-quinolin-4(1H)-one-carboxylic acids

为发现具有抗菌抗肿瘤活性的氟喹诺酮羧酸先导化合物,用芳腙类作为环丙沙星C-7哌嗪基的等排体,设计合成了15个新的1-环丙基-6-氟-7-(芳甲叉肼基)-喹诺酮羧酸(4a^4o)目标化合物,其结构经元素分析和光谱数据确证。目标化合物体外对金黄色葡萄球菌(S.aureus)和大肠埃希菌(E.coli)的抗菌活性弱于对照药环丙沙星,然而对人肝癌(SMMC-7721)株、鼠白血病细胞(L1210)和人白血病细胞(HL60)3种肿瘤细胞株的抑制活性强于环丙沙星,尤其是腙基芳香环上带吸电子取代基的化合物,其抗肿瘤活性显著高于供电子基的活性,其抑制活性与对照药阿霉素相当。这表明C-7哌嗪基的存在有利于提高其抗菌活性而不利于提高抗肿瘤活性,而C-7芳腙基的引入可提高抗肿瘤活性,进一步扩展了氟喹诺酮类化合物结构修饰的范围。

To discover novel antibacterial and antitumor lead compounds derived from fluoroquinolone carboxylic acids,aryl hydrazone moiety as an isosteric replacement of the C-7 piperazine group of ciprofloxacin,fifteen new1-cyclopropyl-6-fluoro-7-arylidenehydrazino-quinolin-4（ 1H）-one-3-carboxylic acids（ 4a-4o） as title compounds were designed and synthesized,respectively. The structures were characterized by elemental analysis and spectral data. The in vitro antibacterial assay of the title compounds against S. aureus and E. coli bacterial strains exhibited poorer activity than parent ciprofloxacin,however,the results of antitumor activity against SMMC-7721,L1210 and HL60 cell lines demonstrated stronger inhibitory activity than parent ciprofloxacin, especially compounds with electron-withdrawing aryl groups were comparable to doxorubicin. It suggests that it is favorable for an improvement of antitumor activity to introduce a functional arylhydrazone group instead of piperazine ring into the 7-position of fluoroquinolone skeleton.