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 antimycobacte

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 IC50 values in the 0.1–8.7 and 0.2–0.7 μM ranges respectively while IC50 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 IC50 values in the 2.5–5 μM and 1.3–≤2.5 μM ranges respectively while MIC and IC50 values for parent LV were 2.5 and 0.8 μM, respectively.

Monomeric and dimeric derivatives of ciprofloxacin and levofloxacin have been synthesized and evaluated for their in vitro antitumor, antibacterial and antimycobacterial activities.Figure optionsDownload as PowerPoint slideHighlights
► Synthesis of dimeric derivatives of Ciprofloxacin and Levofloxacin.
► Compound 3d displayed MIC < 1 nM against MRSA.
► Compound 10d and 7e displayed ICs50 < 10 mM against human cancer cell lines.
► Compound 11f displayed ICs50 < 1 mM against human cancer cell lines.
► Compound 11f displayed an IC50 of 2.5 mM against Mycobacterium Tuberculosis.