Effects of N-1 substituent on the phototoxicity of fluoroquinolone antibiotics: comparison of pefloxacin and difloxacin

Abstract

The photophysics and photochemistry of pefloxacin (PEF), a 1-ethyl-substituted fluoroquinolone (FQ) antibiotic, were studied using transient, steady-state experimental methods and computational methods. The fundamental photoproperties of PEF and its phototoxicity toward lysozyme, a single-chain protein, were compared with those of a 1-fluorophenyl-substituted FQ antibiotic, difloxacin (DIF). The results showed that the phototoxicity was significantly decreased by the insertion of the bulky 1-fluorophenyl substituent (the phototoxicity of DIF was approximately one-quarter of that observed for PEF). This trend was attributed to the lowest lying singlet state with sizeable oscillator strength (f ≥ 0.1) being shifted from 319 nm in PEF to 266 nm in DIF upon the insertion of the bulky substituent at the 1-position, as investigated by using computational methods. In addition, 95% of the solar UV irradiation that reaches the earth’s surface has wavelength > 315 nm. Therefore, reducing the most effective excitation wavelength by optimizing the substituent at the 1-position may be a promising strategy to alleviate the phototoxicity of FQ antibiotics. These findings may be applied to other FQ antibiotics because a large number of phototoxicity studies on FQ antibiotics with different substituents at the 1-position can prove these finding’s effectiveness. Delafloxacin, an FQ antibiotic bearing a chlorine and bulky substituent at the 8- and 1-positions, respectively, exhibits no phototoxicity is the most recent example reported to date. To the best of our knowledge, this is the first transient and steady-state study of the effect of the N-1 substituent on the photochemistry and phototoxicity of FQ antibiotics. These findings will be beneficial to the development of novel FQ antibiotics without phototoxicity.