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 part of a systematic study to optimize the quinolone antibacterials against mycobacteria, we have prepared a series of N-1-phenyl-substituted derivatives to expl...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-07, Vol.38 (15), p.2974-2977
Main Authors: Renau, Thomas E, Sanchez, Joseph P, Shapiro, Martin A, Dever, Julie A, Gracheck, Stephen J, Domagala, John M
Format: Article
Language:English
Subjects:
Anti-Infective Agents - chemical synthesis
Anti-Infective Agents - pharmacology
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Biological and medical sciences
Chemical Phenomena
Chemistry, Physical
Fluoroquinolones
Kinetics
Medical sciences
Microbial Sensitivity Tests
Mycobacterium - drug effects
Mycobacterium fortuitum
Mycobacterium smegmatis
Mycobacterium tuberculosis
Pharmacology. Drug treatments
Piperazines - chemical synthesis
Piperazines - pharmacology
Structure-Activity Relationship
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Summary:The dramatic increase in drug resistant Mycobacterium tuberculosis has caused a resurgence in research targeted toward these organisms. As part of a systematic study to optimize the quinolone antibacterials against mycobacteria, we have prepared a series of N-1-phenyl-substituted derivatives to explore the effect of increasing lipophilicity on potency at this position. The compounds, synthesized by the modification of a literature procedure, were evaluated for activity against Gram-negative and Gram-positive bacteria, Mycobacterium fortuitum and Mycobacterium smegmatis, and the results correlated with log P, pKa, and other attributes. The activity of the compounds against the rapidly growing, less hazardous organism M. fortuitum was used as a measure of M. tuberculosis activity. The results demonstrate that increasing lipophilic character by itself does not correlate with increased potency against mycobacteria. Rather, intrinsic activity against Gram-negative and/or Gram-positive bacteria is the governing factor for corresponding activity against mycobacteria.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00015a021