Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity, and antimicrobial activity.

Fluoroquinolones are potent inhibitors of bacterial topoisomerase II (DNA gyrase). They can also inhibit eukaryotic topoisomerases, which could possibly lead to clastogenicity and/or cellular toxicity. Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the fluoroquinolones and the potential of these compounds to induce micronuclei, a genetic toxicity endpoint. In an effort to identify potent nontoxic quinolone antibacterials, we have examined the structural features of the fluoroquinolones associated with mammalian cell cytotoxicity. An investigation of a wide variety of substituents at the 1, 5, 7, and 8 positions of a quinolone nucleus was conducted. The results indicate that no one position has a controlling effect on the observed cytotoxicity. Instead, a combination of the various substituents contributes to the effects seen. Certain trends were apparent, such as the fact that compounds with pyrrolidines at the R-7 position were more cytotoxic than those with piperazines, and halogens at R-8 (X-position) were associated with more cytotoxicity relative to hydrogen. A general trend also existed between the cytotoxicity of the compounds and their Gram-positive antibacterial activity. A detailed comparison between the various groups and positional variations as they controlled the cytotoxicity and antibacterial activity is presented.