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J Med Chem. 2007 Oct 4;50(20):4868-81. Epub 2007 Aug 28.

Novel substituted (pyridin-3-yl)phenyloxazolidinones: antibacterial agents with reduced activity against monoamine oxidase A and increased solubility.

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AstraZeneca Discovery, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, USA.


Oxazolidinones represent a new and promising class of antibacterial agents. Current research in this area is mainly concentrated on improving the safety profile and the antibacterial spectrum. Oxazolidinones bearing a (pyridin-3-yl)phenyl moiety (e.g., 3) generally show improved antibacterial activity compared to linezolid but suffer from potent monoamine oxidase A (MAO-A) inhibition and low solubility. We now disclose the finding that new analogues of 3 with acyclic substituents on the pyridyl moiety exhibit excellent activity against Gram-positive pathogens, including linezolid-resistant Streptococcus pneumoniae. Generally, more bulky substituents yielded significantly reduced MAO-A inhibition relative to the unsubstituted compound 3. The MAO-A SAR can be rationalized on the basis of docking studies using a MAO-A/MAO-B homology model. Solubility was enhanced with incorporation of polar groups. One optimized analogue, compound 13, showed low clearance in the rat and efficacy against S. pneumoniae in a mouse pneumonia model.

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