title: Identification of 4-substituted 1,2,3-triazoles as novel oxazolidinone antibacterial agents with reduced activity against monoamine oxidase A.
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. Many oxazolidinones, including linezolid (marketed as Zyvox), are inhibitors of monoamine oxidase A (MAO-A), which presents an undesired side effect. Recently, it was found that the 1,2,3-triazole is a good replacement for the conventional acetamide functionality found in oxazolidinones. We now disclose the finding that 1,2,3-triazoles bearing a substituent like methyl, small substituted methyl, bromo, or a linear (sp-hybridized) group at the 4 position (compounds such as 5, 16, 19, and 21) are good antibacterials with reduced or no activity, within the detection limit of the assay, against MAO-A. The results are especially promising for the development of oxazolidinones with an improved safety profile. The MAO-A SAR can be rationalized on the basis of docking studies to a MAO-A/MAO-B homology 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: Marc
authors.initials: M
authors.lastname: Girardot
authors.forename: Gunther
authors.initials: G
authors.lastname: Kern
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Eyermann
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Hales
authors.forename: Rona R
authors.initials: RR
authors.lastname: Ramsay
authors.forename: Michael B
authors.initials: MB
authors.lastname: Gravestock
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006193:Haemophilus influenzae / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D008996:Monoamine Oxidase Inhibitors; D023303:Oxazolidinones; D014230:Triazoles; D008995:Monoamine Oxidase