Design, Synthesis, and Biological Evaluation of Novel 7-[(3 aS,7 aS)-3 a-Aminohexahydropyrano[3,4- c]pyrrol-2(3 H)-yl]-8-methoxyquinolines with Potent Antibacterial Activity against Respiratory Pathogens

J Med Chem. 2018 Aug 23;61(16):7234-7244. doi: 10.1021/acs.jmedchem.8b00644. Epub 2018 Aug 8.


Novel 7-[(3 aS,7 aS)-3 a-aminohexahydropyrano[3,4- c]pyrrol-2(3 H)-yl]-6-fluoro-1-[(1 R,2 S)-2- fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 5 (DS21412020) was designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Compound 5 possessing a trans-fused pyranose ring on the pyrrolidine moiety at the C-7 position of the quinolone scaffold exhibited potent in vitro antibacterial activity against respiratory pathogens, including quinolone-resistant and methicillin-resistant Staphylococcus aureus (QR- MRSA) and quinolone-resistant Escherichia coli (QR- E. coli). Furthermore, compound 5 showed in vivo activity against the experimental murine pneumonia model due to penicillin-resistant Streptococcus pneumoniae ( PRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies. In particular, the reduced lipophilicity and basicity of compound 5 as compared to those of the previously synthesized carba-type compound 4 resulted in a significant reduction in the human ether-a-go-go (hERG) related gene channel inhibition, which have the potential to prolong the QT interval.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology*
  • Drug Design
  • Drug Evaluation, Preclinical / methods
  • Drug Resistance, Bacterial / drug effects
  • ERG1 Potassium Channel / antagonists & inhibitors
  • Escherichia coli / drug effects
  • Female
  • Humans
  • Macaca fascicularis
  • Male
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Mice, Inbred CBA
  • Microbial Sensitivity Tests
  • Pneumococcal Infections / drug therapy
  • Pneumococcal Infections / microbiology
  • Quinolines / chemistry
  • Respiratory Tract Infections / microbiology*
  • Streptococcus pneumoniae / drug effects
  • Streptococcus pneumoniae / pathogenicity


  • Anti-Bacterial Agents
  • ERG1 Potassium Channel
  • KCNH2 protein, human
  • Quinolines