Studies on Prodrugs. 11. Synthesis and Antimicrobial Activity of N-[(4-Methyl-5-methylene-2-oxo-l,3-dioxolan-4-yl)oxy]norfloxacin

The chemical oxidation of N-[(5-methyl-2-oxo-l,3-dioxol-4-yl)methyl]norfloxacin (2) was carried out to afford N-[(4-methyl-5-methylene-2-oxo-l,3-dioxolan-4-yl)oxy]norfloxacin (4). In vitro, 4 exhibited lower activity than that of norfloxacin (NFLX, 1) for both Gram-positive and Gram-negative bacteria. However, in vivo the activity of 4 was higher than that of NFLX. Bioavailability studies in mice showed that 4 liberated a higher concentration of NFLX in plasma than NFLX itself when administered orally. From these data, 4 obtained by the chemical oxidation of 2 functioned as a prodrug of NFLX as well as did 2. The mechanism of the formation of 4 is interpreted in terms of [2,3]-sigmatropic rearrangement.