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

Novel 7-[(3<i>aS</i>,7<i>aS</i>)-3<i>a</i>-aminohexahydropyrano­[3,4-<i>c</i>]­pyrrol-2­(3<i>H</i>)-yl]-6-fluoro-1-[(1<i>R</i>,2<i>S</i>)-2- fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid <b>5</b> (<b>DS21412020</b>) was designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Compound <b>5</b> possessing a <i>trans</i>-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-<i>MRSA</i>) and quinolone-resistant Escherichia coli (QR-E. coli). Furthermore, compound <b>5</b> showed in vivo activity against the experimental murine pneumonia model due to penicillin-resistant Streptococcus pneumoniae (<i>PRSP</i>) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies. In particular, the reduced lipophilicity and basicity of compound <b>5</b> as compared to those of the previously synthesized carba-type compound <b>4</b> 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

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

Novel 7-[(3<i>aS</i>,7<i>aS</i>)-3<i>a</i>-aminohexahydropyrano­[3,4-<i>c</i>]­pyrrol-2­(3<i>H</i>)-yl]-6-fluoro-1-[(1<i>R</i>,2<i>S</i>)-2- fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid <b>5</b> (<b>DS21412020</b>) was designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Compound <b>5</b> possessing a <i>trans</i>-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-<i>MRSA</i>) and quinolone-resistant Escherichia coli (QR-E. coli). Furthermore, compound <b>5</b> showed in vivo activity against the experimental murine pneumonia model due to penicillin-resistant Streptococcus pneumoniae (<i>PRSP</i>) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies. In particular, the reduced lipophilicity and basicity of compound <b>5</b> as compared to those of the previously synthesized carba-type compound <b>4</b> 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

Design, Synthesis, and Biological Evaluations of Novel 7‑[7-Amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-8-methoxyquinolines with Potent Antibacterial Activity against Respiratory Pathogens

Novel 7-[7-amino-7-methyl-5-azaspiro­[2.4]­heptan-5-yl]-6-fluoro-1-[(1<i>R</i>,2<i>S</i>)-2-fluorocyclopropyl]- 8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid <b>2a</b> and <b>2b</b> were designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Among these, compound <b>2a</b> possessing (<i>S</i>)-configuration for the asymmetrical carbon on the pyrolidine moiety at the C-7 position of the quinolone scaffold exhibited potent in vitro antibacterial activity against respiratory pathogens including Gram-positive (<i>Streptococcus pneumoniae</i> and <i>Staphylococcus aureus</i>), Gram-negative (<i>Haemophilus influenzae</i> and <i>Moraxcella catarrhalis</i>), and atypical strains (<i>Chalmydia pneumoniae</i> and <i>Mycoplasma pneumoniae</i>), as well as multidrug-resistant <i>Streptococcus pneumoniae</i> and quinolone-resistant and methicillin-resistant <i>Staphylococcus aureus</i>). Furthermore, compound <b>2a</b> showed excellent in vivo activity against the experimental murine pneumonia model due to multidrug resistant <i>Streptococcus pneumoniae</i> (MDRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies