Chiral DNA gyrase inhibitors. 3. Probing the chiral preference of the active site of DNA gyrase. Synthesis of 10-fluoro-6-methyl-6,7-dihydro-9-piperazinyl- 2H-benzo[a]quinolizin-20-one-3-carboxylic acid analogues

J Med Chem. 2005 Feb 24;48(4):1229-36. doi: 10.1021/jm0401356.

Abstract

In pursuit of an apparent literature anomaly, S- and R-6-methyl-6,7-dihydro-2H-benzo[a]quinolizin-2-one-3-carboxylic acids (12 and 22) were synthesized by an unambiguous route from optically active norephedrines, and their antibacterial potencies were measured. Against Gram-negative microorganisms and DNA gyrase a preference for S-absolute configuration was found whereas R-absolute stereochemistry was more active against Gram-positives. These results are in partial conflict with an earlier report. In an attempt to enhance potency, racemic 10-fluoro-9-piperazinyl (35) and related analogues were synthesized by a novel route. The latter analogues were surprisingly unimproved in potency. The implications of these findings are briefly discussed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Binding Sites
  • DNA Gyrase / chemistry*
  • Gram-Negative Bacteria / drug effects
  • Gram-Positive Bacteria / drug effects
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Quinolizines / chemical synthesis*
  • Quinolizines / chemistry
  • Quinolizines / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors*

Substances

  • Anti-Bacterial Agents
  • Piperazines
  • Quinolizines
  • Topoisomerase II Inhibitors
  • DNA Gyrase