EFFECT OF LIPOPHILICITY AT N-1 ON ACTIVITY OF FLUOROQUINOLONES AGAINST MYCOBACTERIA

The dramatic increase in drug resistant Mycobacterium tuberculosis has caused a resurgence in research targeted toward these organisms. As p art of a systematic study to optimize the quinolone antibacterials aga inst mycobacteria, we have prepared a series of N-1-phenylsubstituted derivatives to explore the effect of increasing lipophilicity on poten cy at this position. The compounds, synthesized by the modification of a literature procedure, were evaluated for activity against Gram-nega tive and Gram-positive bacteria, Mycobacterium fortuitum and Mycobacte rium smegmatis, and the results correlated with log P, pK(a), and othe r attributes. The activity of the compounds against the rapidly growin g, less hazardous organism M. fortuitum was used as a measure of M, tu berculosis activity. The results demonstrate that increasing lipophili c character by itself does not correlate with increased potency agains t mycobacteria. Rather, intrinsic activity against Gram-negative and/o r Gram-positive bacteria is the governing factor for corresponding act ivity against mycobacteria.