1. Pharm Res. (2014) 31:1290–1301 [Epub ahead of print2013 Dec 5]
Pharmacological Characterization of 7-(4-(Piperazin-1-yl)) Ciprofloxacin
Derivatives: Antibacterial Activity, Cellular Accumulation, Susceptibility to
Efflux Transporters, and Intracellular Activity.

Marquez B(1), Pourcelle V, Vallet CM, Mingeot-Leclercq MP, Tulkens PM,
Marchand-Bruynaert J, Van Bambeke F.

Author information: 
(1)Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Avenue E. Mounier 73 bte B1.73.05, 1200,
Brussels, Belgium.

PURPOSE: 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,
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

PMID: 24306327  [PubMed - as supplied by publisher]