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

摘要

Novel 7-[(3aS,7aS)-3a-aminohexahydropyrano[3,4-c]pyrrol-2(3H)-yl]-6-fluoro-1-[(1R,2S)-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.