title: Discovery of (3S)-amino-(4R)-ethylpiperidinyl quinolones as potent antibacterial agents with a broad spectrum of activity and activity against resistant pathogens.
abstract: Novel quinolone antibacterial agents bearing (3S)-amino-(4R)-ethylpiperidines were designed by using low energy conformation analysis and synthesized by applying a conventional coupling reaction of the quinolone nuclei with new piperidine side chains. These compounds were tested in MIC assays and found to be highly potent against Gram-positive and Gram-negative organisms. In particular, the new compounds exhibited high activity against the resistant pathogens Staphylococcus aureus (MRCR) and Streptococcus pneumoniae (PR). Importantly, when the (3S)-amino-(4R)-ethylpiperidinyl quinolones were compared with marketed quinolones sharing the same quinolone nuclei but different side chains at the C-7 position, the new quinolones showed superior activity against Gram-positive organisms, including resistant pathogens.
authors.affiliation: Procter & Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA. hu.xe@pg.com
authors.forename: X Eric
authors.initials: XE
authors.lastname: Hu
authors.forename: Nick K
authors.initials: NK
authors.lastname: Kim
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Gray
authors.forename: Ji-In K
authors.initials: JI
authors.lastname: Almstead
authors.forename: William L
authors.initials: WL
authors.lastname: Seibel
authors.forename: Benoit
authors.initials: B
authors.lastname: Ledoussal
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D027081:DNA Gyrase / Q000737:chemistry / Q000187:drug effects; D004278:DNA, Superhelical / Q000737:chemistry / Q000187:drug effects; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000201:enzymology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004278:DNA, Superhelical; D010880:Piperidines; D015363:Quinolones; D027081:DNA Gyrase