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A novel substituent at the 1-position markedly decreases the phototoxicity of an 8-chloro fluoroquinolone, WQ-2756, in vivo and in vitro



A novel substituent at the 1-position markedly decreases the phototoxicity of an 8-chloro fluoroquinolone, WQ-2756, in vivo and in vitro



Abstracts of the Interscience Conference on Antimicrobial Agents & Chemotherapy 41: 220



WQ-2756, a 1-(5-amino-2, 4-difluorophenyl)-8-chloro quinolone, had a potent antibacterial activity against Gram-positive and -negative bacteria including quinolone-resistant strains. While it has been reported that a halogen atom at the 8-position increases phototoxicity, WQ-2756 surprisingly showed no phototoxicity in murine model (36th ICAAC). We compared the phototoxic potential of WQ-2756 with that of WQ-2763 (1-(2, 4-difluorophenyl)-8-chloro quinolone) to examine the impact of amino substituent at the 1-position on phototoxicity in vivo and in vitro. Female ICR mice (n=6) were given a single intravenous administration of WQ-2756 or WQ-2763 at 20 or 40 mg/kg, followed by UVA irradiation for 4 h (21.6 J/cm2). WQ-2763 showed severe phototoxicity such as erythema and swelling reactions on auricle, but WQ-2756 did not show any phototoxicity. The neutral red uptake assay (lysosomes) and DNA strand-breaking assay (DNA) were used as models of phototoxic injury to the biological sites and components. The phototoxic effects of WQ-2756 on lysosomes and DNA were significantly weaker than those of WQ-2763. These results demonstrate that an amino group at the 1-position has an important role in decreasing the phototoxicity of an 8-halogeno fluoroquinolone.

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