[1,2,4]三嗪并[3,4-h][1,8]萘啶-8-酮-7-羧酸衍生物的设计合成及抗菌和抗细胞增殖活性

Design, synthesis, antibacterial and anti-cell proliferation activities of [1,2,4]triazino[3,4-h][1,8]naphthyridine-8-one-7-carboxylic acid derivatives

为发现新结构氟喹诺酮先导物,基于药效团拼合药物设计原理,用[1,2,4]三嗪核为稠合环,设计合成了新三环氟喹诺酮衍生物[1,2,4]三嗪并[3,4-h][1,8]萘啶-8-酮-7-羧酸目标化合物(5a^5p),结构经光谱数据和元素分析确证,并对其体外抗菌和抗细胞增殖活性进行了评价。结果表明,目标化合物对耐药菌株和SMMC-7721肝癌细胞株有较强的抑制活性。构-效关系显示,供电子基取代的苯基化合物有利于提高抗菌活性,而吸电子基取代的苯基化合物显示出较强的抗肿瘤活性,其中部分化合物的IC50值与对照药阿霉素相当。因此,三嗪稠合的三环氟喹诺酮羧酸作为新的抗菌抗肿瘤新先导物值得关注和进一步的研究。

To discover novel fluoroquinolone lead compounds as possible anti-infective or/and antitumor chemotherapies, combination principle of pharmacophore-based drug design, a series of novel tricyclic fluoro- quinolone title compounds, [ 1,2,4]triazino[3,4-h][1,8]naphthyridine-8-one-7-carboxylic acid derivatives （5a-5p）, were designed and synthesized with a fused [1,2,4]-triazine ring unit. Their structures were characterized by spectral data and elemental analysis and the in vitro antibacterial and anti-cell proliferation activities were also evaluated. The results showed that the tided compounds exhibited more significant inhibitory activities against drug-resistant bacteria （Methicillin-resistant Staphylococcus aureus and multi drug-resistant Escherichia coli strains） and three tested cancer cell lines （human hepatoma SMMC-7721, murine leukemia L1210 and human murine leukemia HL60 cells）. Interestingly, SAR showed that compounds with electron-donating groups attached to benzene ring had stronger antibacterial activity than antitumor activity, but electron-withdrawing compounds displayed more potential antitumor activity than antibacterial activity, especially antitumor activity of nitro compounds was comparable to comparison doxorubicin. Thus, novel triazine-fused tricyclic fluoroqui- nolones as potent anti-infective or/and antitumor lead compounds are valuable to pay attention and for further development.