Novel Substituted (Pyridin-3-yl)phenyloxazolidinones: Antibacterial Agents with Reduced Activity against Monoamine Oxidase A and Increased Solubility

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• 作者：Folkert Reck ; Fei Zhou ; Charles J. Eyermann ; Gunther Kern ; Dan Carcanague ; Georgine Ioannidis ; Ruth Illingworth ; Grace Poon ; Michael B. Gravestock
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：October 4, 2007
• 年：2007
• 卷：50
• 期：20
• 页码：4868 - 4881
• 全文大小：403K
• 年卷期：v.50,no.20(October 4, 2007)
• ISSN：1520-4804

文摘

Oxazolidinones represent a new and promising class of antibacterial agents. Current research in this area ismainly concentrated on improving the safety profile and the antibacterial spectrum. Oxazolidinones bearinga (pyridin-3-yl)phenyl moiety (e.g., 3) generally show improved antibacterial activity compared to linezolidbut suffer from potent monoamine oxidase A (MAO-A) inhibition and low solubility. We now disclose thefinding that new analogues of 3 with acyclic substituents on the pyridyl moiety exhibit excellent activityagainst Gram-positive pathogens, including linezolid-resistant Streptococcus pneumoniae. Generally, morebulky substituents yielded significantly reduced MAO-A inhibition relative to the unsubstituted compound3. The MAO-A SAR can be rationalized on the basis of docking studies using a MAO-A/MAO-B homologymodel. Solubility was enhanced with incorporation of polar groups. One optimized analogue, compound13, showed low clearance in the rat and efficacy against S. pneumoniae in a mouse pneumonia model.