Discovery of (3S)-Amino-(4R)-ethylpiperidinyl Quinolones as Potent Antibacterial Agents with a Broad Spectrum of Activity and Activity against Resistant Pathogens

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 fo...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2003-08, Vol.46 (17), p.3655-3661
Main Authors: Hu, X. Eric, Kim, Nick K, Gray, Jeffrey L, Almstead, Ji-In K, Seibel, William L, Ledoussal, Benoit
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Bacteria - drug effects
Biological and medical sciences
DNA Gyrase - chemistry
DNA Gyrase - drug effects
DNA, Superhelical - chemistry
DNA, Superhelical - drug effects
Drug Resistance, Bacterial
Escherichia coli - enzymology
Gram-Negative Bacteria - drug effects
Gram-Positive Bacteria - drug effects
Medical sciences
Microbial Sensitivity Tests
Models, Molecular
Molecular Conformation
Pharmacology. Drug treatments
Piperidines - chemical synthesis
Piperidines - chemistry
Piperidines - pharmacology
Quinolones - chemical synthesis
Quinolones - chemistry
Quinolones - pharmacology
Stereoisomerism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm030272n