Renau T E, Sanchez J P, Gage J W, Dever J A, Shapiro M A, Gracheck S J, Domagala J M
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
J Med Chem. 1996 Feb 2;39(3):729-35. doi: 10.1021/jm9507082.
The re-emergence of tuberculosis infections which are resistant to conventional drug therapy has demonstrated the need for alternative chemotherapy against Mycobacterium tuberculosis. As part of a study to optimize the quinolone antibacterials against M. tuberculosis, we have prepared a series of N-1- and C-7-substituted quinolones to examine specific structure-activity relationships between modifications of the quinolone at these two positions and activity against mycobacteria. The compounds, synthesized by literature procedures, were evaluated for activity against Mycobacterium fortuitum and Mycobacterium smegmatis as well as Gram-negative and Gram-positive bacteria. The activity of the compounds against M. fortuitum was used as a barometer of M. tuberculosis activity. The results demonstrate that (i) the activity against mycobacteria was related more to antibacterial activity than to changes in the lipophilicity of the compounds, (ii) the antimycobacterial activity imparted by the N-1 substituent was in the order tert-butyl > or = cyclopropyl > 2,4-difluorophenyl > ethyl approximately cyclobutyl > isopropyl, and (iii) substitution with either piperazine or pyrrolidine heterocycles at C-7 afforded similar activity against mycobacteria.
对传统药物疗法耐药的结核感染再度出现，这表明需要有针对结核分枝杆菌的替代化疗方法。作为优化喹诺酮类抗结核药物研究的一部分，我们制备了一系列N-1和C-7位取代的喹诺酮类化合物，以研究喹诺酮类在这两个位置的修饰与抗分枝杆菌活性之间的特定构效关系。通过文献方法合成的这些化合物，针对偶然分枝杆菌、耻垢分枝杆菌以及革兰氏阴性和革兰氏阳性菌进行了活性评估。这些化合物对偶然分枝杆菌的活性被用作结核分枝杆菌活性的晴雨表。结果表明：（i）对分枝杆菌的活性与抗菌活性的关联度高于与化合物亲脂性变化的关联度；（ii）N-1取代基赋予的抗分枝杆菌活性顺序为叔丁基≥环丙基＞2,4-二氟苯基＞乙基≈环丁基＞异丙基；（iii）在C-7位用哌嗪或吡咯烷杂环取代，对分枝杆菌具有相似的活性。
