title: Synthesis and structure-activity relationships of 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolonecarboxylic acid antibacterials having fluorinated 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] substituents.
abstract: A series of novel 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolones bearing fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl substituents at the C-7 position (2-4) was synthesized to obtain potent drugs for infections caused by Gram-positive pathogens, which include resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE). These fluorinated compounds 2-4 exhibited potent antibacterial activity comparable with that of a compound bearing a non-fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidine moiety at the C-7 position (1) and had at least 4 times more potent activity against representative Gram-positive bacteria than ciprofloxacin (CPFX), gatifloxacin (GFLX), or moxifloxacin (MFLX). Among them, the 7-[(3S,4R)-4-(1-aminocyclopropan-1-yl)-3-fluoropyrrolidin-1-yl] derivative 3 (=DQ-113), which showed favorable profiles in preliminary toxicological and nonclinical pharmcokinetic studies, exhibited potent antibacterial activity against clinically isolated resistant Gram-positive pathogens.
authors.affiliation: Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co. Ltd., 16-13, Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan. inagaeeb@daiichipharm.co.jp
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Inagaki
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyauchi
authors.forename: Rie N
authors.initials: RN
authors.lastname: Miyauchi
authors.forename: Haruko C
authors.initials: HC
authors.lastname: Kawato
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohki
authors.forename: Norikazu
authors.initials: N
authors.lastname: Matsuhashi
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kawakami
authors.forename: Hisashi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Takemura
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D003521:Cyclopropanes; C456082:DQ113; D015363:Quinolones