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 hirae 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 IC(50) values in the 0.1-8.7 and 0.2-0.7 μM ranges respectively while IC(50) values for parent CP and LV ranged from 89 to 476 μM and from 67 to 622 μM 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 CP 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 IC(50) values in the 2.5-5 μM and 1.3-≤ 2.5 μM ranges respectively while MIC and IC(50) values for parent LV were 2.5 and 0.8 μM, respectively.
Université de Toulouse, UPS, Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique, Groupe de RMN Biomédicale, 118 route de Narbonne, F-31062 Toulouse Cedex 9, France. azema@chimie.ups-tlse.fr
Joëlle
J
Azéma
Brigitte
B
Guidetti
Alexander
A
Korolyov
Robert
R
Kiss
Christine
C
Roques
Patricia
P
Constant
Mamadou
M
Daffé
Myriam
M
Malet-Martino
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy; D045744:Cell Line, Tumor; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D019281:Dimerization; D024841:Fluoroquinolones / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D009369:Neoplasms / Q000188:drug therapy; D015242:Ofloxacin / Q000031:analogs & derivatives* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D024841:Fluoroquinolones; D002939:Ciprofloxacin; D064704:Levofloxacin; D015242:Ofloxacin