Synthesis and antibacterial activity of new tetracyclic quinolone antibacterials

J Med Chem. 1992 Jan;35(1):94-9. doi: 10.1021/jm00079a011.


A series of 8-substituted-9,1-(epoxymethano)-7-fluoro-5-oxo-5H- thiazolo[3,2-a]quinoline-4-carboxylic acids having a novel tetracyclic structure was synthesized and tested for antibacterial activity. The nature of the heteroatom (N, O, or S) substituted at the 8-position had little influence on the antibacterial activity. Among the six pyrrolidinyl derivatives and the five piperazinyl derivatives, the 8-(3-hydroxy-1-pyrrolidinyl) derivative 6h and the hydrochloride of the 8-(4-methyl-1-piperazinyl) derivative 6l showed the most potent activity against both Gram-positive and Gram-negative bacteria. Against nalidixic acid resistant strains, isolated from Escherichia coli KC-14, compound 6h was less potent than 6l. Replacement of the piperazinyl nitrogen atom by a carbon atom, an oxygen atom, or a sulfur atom (corresponding to the piperidino, morpholino, or thiomorpholino group, respectively) enhanced the activity against Gram-positive bacteria, but reduced the activity against Gram-negative bacteria. Compound 6l also showed potent in vivo antibacterial activity against Gram-positive and Gram-negative bacteria, and did not cause convulsions in mice with the concomitant administration of fenbufen. Replacement of the carboxy group by a sulfonic acid group in 6l resulted in a complete loss of antibacterial activity.

MeSH terms

  • Animals
  • Anti-Infective Agents / chemical synthesis*
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / therapeutic use
  • Escherichia coli
  • Gram-Negative Bacteria / drug effects
  • Gram-Positive Bacteria / drug effects
  • Male
  • Mice
  • Microbial Sensitivity Tests
  • Quinolones / chemical synthesis*
  • Quinolones / chemistry
  • Quinolones / therapeutic use
  • Structure-Activity Relationship


  • Anti-Infective Agents
  • Quinolones