title: Pharmacological characterization of 7-(4-(Piperazin-1-yl)) ciprofloxacin derivatives: antibacterial activity, cellular accumulation, susceptibility to efflux transporters, and intracellular activity.
abstract: OBJECTIVE
  To evaluate pharmacological properties (antibacterial activity; accumulation in phagocytic cells; activity against intracellular bacteria; susceptibility to fluoroquinolone efflux transporters) of ciprofloxacin derivatives modified at C-7 of the piperazine ring.
  
  
  METHODS
  N-acetyl- (1), N-benzoyl- (2), N-ethyl- (3), and N-benzyl- (4) ciprofloxacin were synthesized. MICs against Escherichia coli and Staphylococcus aureus were determined following CLSI guidelines. Cellular accumulation, subcellular distribution, and intracellular activity (towards S. aureus and Listeria monocytogenes) were determined in J774 mouse macrophages. Efflux in bacteria (NorA [S. aureus], Lde [L. monocytogenes]) and in macrophages (Mrp4) was assessed using the corresponding inhibitors reserpine and gemfibrozil, respectively.
  
  
  RESULTS
  All derivatives were active, though less than ciprofloxacin. 2 and 3 accumulated 2-3 fold more than ciprofloxacin in mouse macrophages but remained substrates for efflux by Mrp4. 4 was insensitive to NorA and Lde, accumulated approx 50-fold more than ciprofloxacin in macrophages, was barely affected by Mrp4, localized in the soluble fraction of cells, and was equipotent to ciprofloxacin against intracellular bacteria.
  
  
  CONCLUSIONS
  Benzyl substitution at C7 markedly affects the pharmacological profile of ciprofloxacin with respect to recognition by efflux transporters and cellular accumulation. N-benzyl-ciprofloxacin may serve as basis for designing molecules with higher intrinsic activity while remaining poorly susceptible to efflux.
authors.affiliation: Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier 73 bte B1.73.05, 1200, Brussels, Belgium.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Marquez
authors.forename: Vincent
authors.initials: V
authors.lastname: Pourcelle
authors.forename: Coralie M
authors.initials: CM
authors.lastname: Vallet
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Mingeot-Leclercq
authors.forename: Paul M
authors.initials: PM
authors.lastname: Tulkens
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Marchand-Bruynaert
authors.forename: Françoise
authors.initials: F
authors.lastname: Van Bambeke
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001692:Biological Transport; D002460:Cell Line; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin