Dipartimento di Biotecnologie Mediche, Università di Siena, Policlinico Santa Maria alle Scotte, Viale Bracci 1, 53100 Siena, Italy.
Tuberculosis (Edinb). 2013 Jul;93(4):405-11. doi: 10.1016/j.tube.2013.02.017. Epub 2013 Mar 22.
A set of 21 new fluoroquinolones bearing an aromatic or heteroaromatic moiety at C-7 and an alkyl group at N-1 were synthesized based on the lead structure of pirfloxacin and tested in vitro against Mycobacterium tuberculosis (M. tuberculosis) H37Rv by MIC determination in liquid medium. Among the synthesized compounds, 1-(tert-butyl)-6-fluoro-7-(4-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2o) and 1-(tert-butyl)-6-fluoro-7-(pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2n) were found to be the most active ones against M. tuberculosis H37Rv with the same MICs of reference compounds ciprofloxacin (CFX) and levofloxacin (LFX). MICs of 2o and 2n were determined for fluoroquinolone-sensitive and fluoroquinolone-resistant M. tuberculosis clinical isolates and 2o was the most active compound with up 4-fold difference of MIC with respect to CFX. The activity of 2o was also tested at the concentration of 16 μg/mL against M. tuberculosis H37Rv in infected murine macrophages. The results showed a 4-fold decrease in viable count of cell-associated mycobacteria with respect to untreated controls after 48 h of drug incubation.
基于左氧氟沙星的先导结构，我们设计并合成了一组 21 种新型氟喹诺酮类化合物，这些化合物在 C-7 位带有芳基或杂芳基，在 N-1 位带有烷基，然后通过液体介质中的 MIC 测定法，对结核分枝杆菌（M. tuberculosis）H37Rv 进行了体外测试。在所合成的化合物中，1-（叔丁基）-6-氟-7-（4-羟基苯基）-4-氧代-1,4-二氢喹啉-3-羧酸（2o）和 1-（叔丁基）-6-氟-7-（吡啶-3-基）-4-氧代-1,4-二氢喹啉-3-羧酸（2n）对结核分枝杆菌 H37Rv 的活性最强，与对照药物环丙沙星（CFX）和左氧氟沙星（LFX）的 MIC 相同。我们还测定了 2o 和 2n 对氟喹诺酮敏感和氟喹诺酮耐药结核分枝杆菌临床分离株的 MIC，2o 的活性最高，与 CFX 的 MIC 相差 4 倍。我们还在感染的鼠巨噬细胞中，以 16 μg/mL 的浓度测试了 2o 对结核分枝杆菌 H37Rv 的活性。结果显示，与未处理的对照组相比，药物孵育 48 小时后，细胞相关分枝杆菌的活菌数减少了 4 倍。
