Synthesis of lipophilic dimeric C-7/C-7-linked ciprofloxacin and C-6/C-6-linked levofloxacin derivatives. Versatile in vitro biological evaluations of monomeric and dimeric fluoroquinolone derivatives as potential antitumor, antibacterial or antimycobacterial agents

The synthesis of C-7/C-7-linked ciprofloxacin (CP) and C-6/C-6-linked levofloxacin (LV) derivatives with modulated lipophilicity is described herein. The synthesized compounds, along with the monomeric analogs described previously, were evaluated in vitro for (i) their growth inhibitory effect against five human cancer cell lines, (ii) their antibacterial activity against Gram-positive Staphylococcus aureus and Enterococcus hi roe and Gram-negative Escherichia coli and Pseudomonas aeruginosa strains and (iii) their antimycobacterial activity. The most efficient derivatives as antiproliferative agents (C-7/C-7-linked CP 7e and C-6/C-6-linked LV 11f) displayed IC50 values in the 0.1-8.7 and 0.2-0.7 mu M ranges respectively while IC50 values for parent CP and LV ranged from 89 to 476 mu M and from 67 to 622 mu M respectively depending on the cell line. A specific antibacterial activity against S. aureus was found for the monomeric and dimeric derivatives of CP. The most efficient derivative against S. aureus (monomeric oxoethyloctanoate CF derivative 3d) displayed MIC <1 nM. Monomeric alkanoyloxymethyl LV esters (9a,c,e,f) and C-6/C-6-linked LV derivatives (11f h) were the most efficient derivatives as antimycobacterial agents with MIC and IC50 values in the 2.5-5 mu M and 1.3-<= 2.5 mu M ranges respectively while MIC and IC50 values for parent LV were 2.5 and 0.8 mu M, respectively. (C) 2011 Elsevier Masson SAS. All rights reserved.