New Findings on the Structure-Phototoxicity Relationship and Photostability of Fluoroquinolones with Various Substituents at Position 1

Abstract

The present study examined the phototoxicities of a series of 7-(3-aminopyrrolidinyl) quinolones containing various substituents at position 1 (in which the substituent at R8 is a hydrogen or a halogen) by use of a mouse model. For the 7-(3-aminopyrrolidinyl) quinolones with a halogen atom at position 8, well-known substituent groups such as a cyclopropyl, an ethyl, or a difluorophenyl at position 1 were found to be responsible for severe phototoxicity. However, when an aminodifluorophenyl or an isoxazolyl group was placed at position 1, even 8-halogeno quinolones were found to be mildly phototoxic. This is the first report of 8-halogeno quinolones that are not severely phototoxic. Two structurally similar 8-chloro quinolones (the 1-aminodifluorophenyl 8-chloro quinolone and the 1-difluorophenyl 8-chloro quinolone) were investigated further. The former was mildly phototoxic; the latter was severely phototoxic. We demonstrate that these two 8-chloro quinolones have practically the same areas under the concentration-time curves from 0 to 4 h in auricular tissue, suggesting that the mild phototoxicity is not due to pharmacokinetic instability. The rates of UV photodegradation of these compounds were also measured. We found that these two quinolones photodegrade at similar rates, suggesting that the mild phototoxicity is not attained through increased photostability. In conclusion, the phototoxic potentials of fluoroquinolones are influenced not only by the substituent at position 8 but also by that at position 1 (a new finding from this study). We also discovered a mildly phototoxic 8-chloro quinolone which did not have increased photostability.

Photoinduced Superoxide Radical Anion and Singlet Oxygen Generation in the Presence of Novel Selenadiazoloquinolones (An EPR Study)

“…The phototoxicity of quinolones is controlled by different mechanisms influenced by the quinolone structure (8,13,14). The irradiated fluoroquinolones may induce DNA damage via reaction pathways dependent on different factors (13,15), hence, a substantial effort has been made to investigate the structure-phototoxicity relationship of quinolones (9,(16)(17)(18)(19). The photoinduced generation of reactive oxygen species (ROS; e.g.…”

Fluoroquinolone Photodegradation Influences Specific Basophil Activation

“…These results could be explained in terms of photostability since both FQs, although they present the same basic structure, show a different photochemical behavior due to different substituents [1,2]. Even though the presence of a fluorine atom in C-6 makes both drugs somewhat photoreactive, the degree to which the molecules are photolabile is modulated by substituents and is directly related to the electronegativity of the substituent at C-8 [3,4]. When we analyzed the photostability in aqueous solution we observed a similar behavior for both FQs.…”

“…UV radiation induces their photodegradation, which is modulated by the nature and position of the substituents attached to the quinolone skeleton [1,2]. For example, the presence of a halogen, as in fluoroquinolones (FQs), seems to be associated with a higher phototoxic potential [3,4]. Photodecomposition may involve a variety of photochemical processes, such as generation of singlet oxygen, production of superoxide, defluorination, decarboxylation at C-3, or oxidation of the amino group at C-7 [1,2,4].…”

Combined Use of In Vitro Phototoxic Assessments and Cassette Dosing Pharmacokinetic Study for Phototoxicity Characterization of Fluoroquinolones

“…However, the skin photosensitivity of GFLX was not observed in a double-blind, placebo-and positive-controlled study (35). In addition to the previous clinical trials, structure-activity and structure-side-effect relationships for FQs were examined in in vitro and in vivo phototoxic studies (36,37), and, in particular, the substituent groups at the eight position of FQs were reported to play a key role in phototoxicity of FQs on the basis of their structure-phototoxicity relationships (15,16). A halogen atom at the eight position exhibited potent phototoxic potential whereas a methoxy group at the eight position had less phototoxic potential.…”