STRUCTURE-ACTIVITY-RELATIONSHIPS OF THE QUINOLONE ANTIBACTERIALS AGAINST MYCOBACTERIA - EFFECT OF STRUCTURAL-CHANGES AT N-1 AND C-7

The re-emergence of tuberculosis infections which are resistant to con ventional drug therapy has demonstrated the need for alternative chemo therapy against Mycobacterium tuberculosis. As part of a study to opti mize the quinolone antibacterials against M. tuberculosis, we have pre pared a series of N-1- and C-7-substituted quinolones to examine speci fic structure-activity relationships between modifications of the quin olone at these two positions and activity against mycobacteria. The co mpounds, synthesized by Literature procedures, were evaluated for acti vity against Mycobacterium fortuitum and Mycobacterium smegmatis as we ll as Gram-negative and Gram-positive bacteria. The activity of the co mpounds against M. fortuitum was used as a barometer of M. tuberculosi s activity. The results demonstrate that (i) the activity against myco bacteria was related more to antibacterial activity than to changes in the lipophilicity of the compounds, (ii) the antimycobacterial activi ty imparted by the N-1 substituent was in the order tert-butyl greater than or equal to cyclopropyl > 2,4-difluorophenyl > ethyl approximate to cyclobutyl > isopropyl, and (iii) substitution with either piperaz ine or pyrrolidine heterocycles at C-7 afforded similar activity again st mycobacteria.