Studies on prodrugs. 11. Synthesis and antimicrobial activity of N-[(4-methyl-5-methylene-2-oxo-1,3-dioxolan-4-yl)oxy]norfloxacin

J Med Chem. 1989 Mar;32(3):671-4. doi: 10.1021/jm00123a029.

Abstract

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.

MeSH terms

  • Animals
  • Anti-Infective Agents / chemical synthesis*
  • Anti-Infective Agents / pharmacology
  • Chemical Phenomena
  • Chemistry
  • Dioxolanes / chemical synthesis*
  • Dioxolanes / pharmacology
  • Dioxoles / chemical synthesis*
  • Escherichia coli Infections / drug therapy
  • Gram-Negative Bacteria / drug effects
  • Gram-Positive Bacteria / drug effects
  • Mice
  • Microbial Sensitivity Tests
  • Norfloxacin / analogs & derivatives*
  • Norfloxacin / chemical synthesis
  • Norfloxacin / pharmacology
  • Prodrugs / chemical synthesis*
  • Prodrugs / pharmacology
  • Structure-Activity Relationship

Substances

  • Anti-Infective Agents
  • Dioxolanes
  • Dioxoles
  • Prodrugs
  • N-((4-methyl-5-methylene-2-oxo-1,3-dioxolan-4-yl)oxy)norfloxacin
  • Norfloxacin