Structure-activity relationships of quinolone agents against mycobacteria: effect of structural modifications at the 8 position.
Structure-activity relationships of quinolone agents against mycobacteria: effect of structural modifications at the 8 position.
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喹诺酮类药物抗分枝杆菌的构效关系：8位结构修饰的影响。
DOI：
10.1128/aac.40.10.2363
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Reynolds,RC
中科院分区：
文献类型：
--
作者：
Renau,TE;Gage,JW;Dever,JA;Roland,GE;Joannides,ET;Shapiro,MA;Sanchez,JP;Gracheck,SJ;Domagala,JM;Jacobs,MR;Reynolds,RC
作为研究的一部分，已经制备了一系列在 8 位具有取代基的喹诺酮类药物，以检查该位置的结构修饰与抗分枝杆菌活性之间的关系。这些化合物按照文献中描述的程序制备，并评估其针对偶发分枝杆菌和耻垢分枝杆菌的活性。化合物针对这两种生物体的活性被用作结核分枝杆菌活性的量度。结果表明，8位对抗分枝杆菌活性的贡献取决于N-1处的取代基，并且顺序为(i)当N-1是环丙基时，COMe大约CBr>CCI>CH大约CF大约COEt>N>CCF3； (ii)当N-1为2，4-二氟苯基时，N近似CH>CF>COMe； (iii)当N-1是叔丁基时，N>或=CH； (iv)当N-1是乙基时N>CH。一般来说，无论 8 位的取代模式如何，在 C-7 处具有哌嗪取代的衍生物对分枝杆菌的活性略低于具有吡咯烷取代的类似物。评估了几种最好的化合物的潜在副作用以及针对金分枝杆菌、鸟分枝杆菌-M 的活性。细胞内和结核分枝杆菌。这些药物表现出与阳性对照环丙沙星和司帕沙星相似或更好的生物学特征。
A series of quinolones with substitutions at the 8 position has been prepared as part of a study to examine the relationship between structural modifications at this position and activity against mycobacteria. The compounds were prepared by procedures described in the literature and were evaluated for their activities against Mycobacterium fortuitum and Mycobacterium smegmatis. The activities of the compounds against these two organisms were used as a measure of Mycobacterium tuberculosis activity. The results demonstrate that the contribution of the 8 position to antimycobacterial activity was dependent on the substituent at N-1 and was in the order (i) COMe approximately CBr > CCI > CH approximately CF approximately COEt > N > CCF3 when N-1 was cyclopropyl; (ii) N approximately CH > CF > COMe when N-1 was 2,4-difluorophenyl; (iii) N > or = CH when N-1 was tert-butyl; and (iv) N > CH when N-1 was ethyl. In general, derivatives with piperazine substitutions at C-7 were slightly less active against mycobacteria than the analogs with pyrrolidine substitutions, regardless of the pattern of substitution at the 8 position. Several of the best compounds were evaluated for their potential side effects as well as their activities against Mycobacterium aurum, Mycobacterium avium-M. intracellulare, and M. tuberculosis. These agents exhibited biological profiles similar to or better than those of the positive controls ciprofloxacin and sparfloxacin.