Fluoroquinolone Antimicrobials: Singlet Oxygen, Superoxide and Phototoxicity

Abstract

The fluoroquinolone antibacterial agents possess photo‐sensitizing properties that lead to phototoxic responses in both human and animal subjects. The phototoxicity order reported in humans is: fleroxacin > lomefloxacin, pefloxacin > ciprofloxacin ≫ enoxacin, norfloxacin and ofloxacin. Studies both in vivo and in vitro have related this phototoxicity to the generation of reactive oxygen species including hydrogen peroxide and the hydroxyl radical. We determined the quantum yields of singlet oxygen generation (φ Δ,) by detection of the singlet oxygen (1 O 2) luminescence at 1270 tun for several fluoroquinolones, naphthyridines and other structurally related compounds. All the fluoroquinolones examined have low φ Δ values ranging from 0.06 to 0.09 in phosphate buffer at pD 7.5. We also determined the 1 O 2 quenching constants for these compounds and their values were on the order of 10 6M−1 s 1, except for lomefloxacin whose rate constant was 1.8 × 10 7M−1 s−1. The φ Δ values were significantly decreased in a solvent of lower polarity such as methanol (0.007 ≤φ Δ≤ 0.02). The production of 1 O 2 by these antibiotics did not correlate with the order reported for their phototoxicity. We also measured the photogeneration (λ > 300 nm) of superoxide by these antibacterials in dimethylsulfoxide using electron paramagnetic resonance and the spin trap 5,5‐dimethyl‐l‐pyrroiine N‐oxide. Although there is not a one‐to‐one correspondence between the relative rates of superoxide generation and the phototoxicity ranking of the fluoroquinolones, the more phototoxic compounds tended to produce superoxide at a faster rate. Nevertheless, the magnitudes of the observed differences do not appear sufficient to explain the range of fluoroquinolone phototoxicity potencies in human and animal subjects in general and the high activity of fleroxacin and lomefloxacin in particular. For these latter drugs the photoinduced loss of the F 8 atom as fluoride and the concomitant generation of a highly reactive carbene at C‐8 provide a more plausible mechanism for their potent phototoxic and photocarcinogenic properties.