Studies on prodrugs. 11. Synthesis and antimicrobial activity of N-[(4-methyl-5-methylene-2-oxo-1,3-dioxolan-4-yl)oxy]norfloxacin .
The chemical oxidation of N-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl] norfloxacin (2) was carried out to afford N-[(4-methyl-5-methylene-2-oxo-1,3-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.
Kondo
H
H
Pharmaceuticals Research Center, Kanebo Ltd., Osaka, Japan.
Sakamoto
F
F
Uno
T
T
Kawahata
Y
Y
Tsukamoto
G
G
D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000494:pharmacology; D004149:Dioxoles / Q000138:chemical synthesis*; D004927:Escherichia coli Infections / Q000188:drug therapy; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D009643:Norfloxacin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D004148:Dioxolanes; D004149:Dioxoles; D011355:Prodrugs; C058715:N-((4-methyl-5-methylene-2-oxo-1,3-dioxolan-4-yl)oxy)norfloxacin; D009643:Norfloxacin