Synthesis and antibacterial activity of a new series of tetracyclic pyridone carboxylic acids

J Med Chem. 1993 Sep 3;36(18):2621-6. doi: 10.1021/jm00070a005.

Abstract

A series of novel tetracyclic pyridone carboxylic acids replacing the 10-position oxygen atom of 9,1-(epoxymethano)-7-fluoro-8-(4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo [3,2-alpha]quinoline-4-carboxylic acid by imino groups (NR; R = Me, Et, c-Pr, allyl, Ph, benzyl), a sulfur atom, or a carbonyl group was prepared and evaluated for antibacterial activity and inhibitory activity on DNA gyrase isolated from E. coli KL-16. The in vitro antibacterial potency and DNA gyrase inhibitory activity were found to be in the following order: NMe > or = O > S >> C = O. Moreover, a methyl group was the optimal alkyl substituent at the 10-position nitrogen atom for antibacterial activity and for DNA gyrase inhibitory activity. 7-Fluoro-9,1-[(N-methylimino)methano]-8- (4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-alpha]quinoline-4-carboxy lic acid (10-NCH3) showed potent in vivo antibacterial activity.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anti-Infective Agents*
  • Bacterial Infections / drug therapy
  • Carboxylic Acids / chemical synthesis*
  • Carboxylic Acids / pharmacology
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology
  • Fluoroquinolones*
  • Gram-Negative Bacteria / drug effects*
  • Gram-Positive Bacteria / drug effects*
  • Male
  • Mice
  • Molecular Structure
  • Piperazines*
  • Pseudomonas aeruginosa / drug effects
  • Pyridones / chemical synthesis*
  • Pyridones / pharmacology
  • Quinolines / chemical synthesis*
  • Quinolines / pharmacology
  • Quinolones*
  • Staphylococcus aureus / drug effects
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacology
  • Topoisomerase II Inhibitors

Substances

  • Anti-Infective Agents
  • Carboxylic Acids
  • Fluoroquinolones
  • Piperazines
  • Pyridones
  • Quinolines
  • Quinolones
  • Thiazoles
  • Topoisomerase II Inhibitors
  • tetracyclic quinolone No. 5290