title: Novel substituted (pyridin-3-yl)phenyloxazolidinones: antibacterial agents with reduced activity against monoamine oxidase A and increased solubility.
abstract: 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.
authors.affiliation: AstraZeneca Discovery, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, USA. folkert.reck@astrazeneca.com
authors.forename: Folkert
authors.initials: F
authors.lastname: Reck
authors.forename: Fei
authors.initials: F
authors.lastname: Zhou
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Eyermann
authors.forename: Gunther
authors.initials: G
authors.lastname: Kern
authors.forename: Dan
authors.initials: D
authors.lastname: Carcanague
authors.forename: Georgine
authors.initials: G
authors.lastname: Ioannidis
authors.forename: Ruth
authors.initials: R
authors.lastname: Illingworth
authors.forename: Grace
authors.initials: G
authors.lastname: Poon
authors.forename: Michael B
authors.initials: MB
authors.lastname: Gravestock
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D024881:Drug Resistance, Bacterial; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006801:Humans; D000069349:Linezolid; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D011725:Pyridines; D008995:Monoamine Oxidase; D000069349:Linezolid