title: 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.
abstract: Novel 7-[7-amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]- 8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2a and 2b were designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Among these, compound 2a possessing (S)-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 (Streptococcus pneumoniae and Staphylococcus aureus), gram-negative (Haemophilus influenzae and Moraxcella catarrhalis), and atypical strains (Chalmydia pneumoniae and Mycoplasma pneumoniae), as well as multidrug-resistant Streptococcus pneumoniae and quinolone-resistant and methicillin-resistant Staphylococcus aureus). Furthermore, compound 2a showed excellent in vivo activity against the experimental murine pneumonia model due to multidrug resistant Streptococcus pneumoniae (MDRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies.
authors: R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. odagiri.takashi.fb@daiichisankyo.co.jp
authors: Takashi
authors: T
authors: Odagiri
authors: Hiroaki
authors: H
authors: Inagaki
authors: Yuichi
authors: Y
authors: Sugimoto
authors: Masatoshi
authors: M
authors: Nagamochi
authors: Rie N
authors: RN
authors: Miyauchi
authors: Junichi
authors: J
authors: Kuroyanagi
authors: Takahiro
authors: T
authors: Kitamura
authors: Satoshi
authors: S
authors: Komoriya
authors: Hisashi
authors: H
authors: Takahashi
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D024841:Fluoroquinolones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D006193:Haemophilus influenzae / Q000187:drug effects; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D015363:Quinolones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000382:microbiology; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects
chemical_list: C581003:7-(7-amino-7-methyl-5-azaspiro(2.4)hept-5-yl)-6-fluoro-1-(2-fluorocyclopropyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D015363:Quinolones; D013141:Spiro Compounds