Significance of the methyl group on the oxazine ring of ofloxacin derivatives in the inhibition of bacterial and mammalian type II topoisomerases.

A study was made of the correlation between the in vitro inhibitory effects of several quinolones, including four ofloxacin derivatives, on bacterial DNA gyrase from Escherichia coli KL-16 and on topoisomerase II from fetal calf thymus. No correlation was observed between the inhibitions of DNA gyrase activity and topoisomerase II activity. On the other hand, the inhibitory effects of these quinolones against topoisomerase II were closely correlated with their inhibition of cell growth. Furthermore, among the oxazine derivatives tested, the derivative with a methyl group at position 3 in an S configuration showed the highest activity against DNA gyrase and derivatives without a methyl group on the oxazine ring were more potent against topoisomerase II than those with a methyl group. Among these derivatives, DR-3355, the S isomer of ofloxacin, showed the highest activity against DNA gyrase and low activity against topoisomerase II. These results indicate that the methyl group on the oxazine ring plays an important role in the inhibitory activities of ofloxacin derivatives for these enzymes.