5-Amino-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid (PD 124,816). Synthesis and biological evaluation of a new class of quinolone antibacterials

Drugs Exp Clin Res. 1988;14(7):453-60.

Abstract

A series of 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acids with piperazinyl or pyrrolidinyl side-chains appended at C7 were prepared to test the effect of the 5-amino group on the biological and physicochemical properties of these quinolones. The target compounds were synthesized from 2-nitro-3,4,5,6-tetrafluorobenzoic acid and were tested against a variety of Gram-negative and Gram-positive bacteria and the bacterial enzyme DNA gyrase, using standard microtitration techniques. The results are compared to reference quinolones such as ciprofloxacin. The 5-amino derivatives were significantly more potent (2-16 times) than their non-amino analogues. Alkylation or acylation of the 5-amino group reduced potency dramatically. The 5-amino group was neither basic nor nucleophilic. 5-Amino-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl- 6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (PD 124,816) was selected as the best compound in this study.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Infective Agents / chemical synthesis*
  • Anti-Infective Agents / pharmacology
  • Anti-Infective Agents / therapeutic use
  • Bacteria / drug effects
  • Escherichia coli Infections / drug therapy*
  • Fluoroquinolones*
  • Indicators and Reagents
  • Mice
  • Microbial Sensitivity Tests
  • Quinolones / chemical synthesis*
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Anti-Infective Agents
  • Fluoroquinolones
  • Indicators and Reagents
  • Quinolones
  • PD 124816