Influence of fluorine atoms on reactive oxygen species-mediated degradation of ophthalmic fluoroquinolones. Kinetic and cytotoxicity studies

Abstract

Fluoroquinolones have been attractive broad-spectrum antibiotics for ophthalmic application. However, they have shown phototoxicity as a significant side effect, which is strongly dependent on fluoroquinolone structure and some environment conditions. Beyond their photo-reactivity, an indirect light-induced process deserves to be considered. The photosensitized action of molecules present in the ocular organ, such as Riboflavin, may produce reactive oxygen species (ROS) that could degrade fluoroquinolones. As a consequence, the antibiotics may lose their therapeutic action and/or produce degradation products with harmful effects on health.In this contribution, a kinetic analysis of ROS-mediated degradation processes of ophthalmic quinolones is addressed. Further, considering the evidence towards the structure-modulated phototoxicity, we evaluated the influence of structural fluorine atoms on these processes. The non-fluorinated precursor Nalidixic Acid and the fluoroquinolones (Ciprofloxacin, Norfloxacin and Lomefloxacin) were selected for this study. Cytotoxicity experiments in Vero cells were performed in order to investigate the potential toxicity of the ROS-mediated degradation products.Our results suggest that quinolones may be degraded by ROS and these processes are regulated by the ionization state of quinolone and the presence of fluorine atoms in their structure. Both effects increase the electron donor ability of the quinolones, which favor electron transfer processes and increase their reactivity towards species with an electrophilic character. Interestingly, this fluorine-dominated effect has been recently called “fluoromaticity”.Cytotoxicity assays indicated that neither the Qs nor their ROS-mediated degradation products presented injury on Vero cells under the current experimental conditions.