title: Antibacterial oxazolidinone analogues having a N-hydroxyacetyl-substituted seven-membered [1,2,5]triazepane or [1,2,5]oxadiazepane C-ring unit.
abstract: We synthesized a series of oxazolidinone analogues bearing a N-hydroxyacetyl-substituted [1,2,5]triazepane or [1,2,5]oxadiazepane C-ring unit as homologues of an earlier drug candidate, eperezolid. Several of these compounds exhibited potent in vitro antibacterial activities towards not only Gram-positive, but also Gram-negative and linezolid-resistant pathogens. Compounds 21a and 21b, bearing a thiocarbamate side chain, showed high in vivo activity against methicillin-resistant Staphylococcus aureus SR3637, together with a promising safety profile in terms of weak inhibition of monoamine oxidase and cytochrome P450 isozymes.
authors.affiliation: Research Foundation Itsuu Laboratory, 2-28-10 Tamagawa, Tokyo 158-0094, Japan. hsuzuki@itsuu.or.jp
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Iwao
authors.initials: I
authors.lastname: Utsunomiya
authors.forename: Koichi
authors.initials: K
authors.lastname: Shudo
authors.forename: Norio
authors.initials: N
authors.lastname: Fukuhara
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Iwaki
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Yasukata
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism; D023303:Oxazolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D013203:Staphylococcal Infections / Q000382:microbiology / Q000517:prevention & control*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D023303:Oxazolidinones; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D008995:Monoamine Oxidase