title: Design, synthesis, and structure-activity relationship studies of highly potent novel benzoxazinyl-oxazolidinone antibacterial agents.
abstract: A series of novel benzoxazinyl-oxazolidinones bearing nonaromatic heterocycle or aryl groups were designed and synthesized. Their in vitro and in vivo antibacterial activities were investigated. Most of the (3S, 3aS) biaryl benzoxazinyl-oxazolidinones exhibited potent activity against Gram-positive pathogens. SAR trends were observed; a pyridyl C ring was preferable to other 5- or 6-member aryl C rings, while fluorine substitution on the B ring generated derivatives with reduced activity. Various substituent group positions on the pyridyl ring were also evaluated. The resulting compounds displayed excellent activity against linezolid-resistant strains. Compound 45 exhibited excellent in vitro activity, with a MIC value of 0.25-0.5 μg/mL against MRSA and an activity against linezolid-resistant strains of 8-16-fold higher potency than linezolid. In a MRSA systemic infection model, compound 45 displayed an ED(50) < 5.0 mg/kg, a potency that is nearly 3-fold better than that of linezolid. This compound also showed excellent pharmacokinetic profiles, with a half-life of more than 5 h as well as an oral bioavailability of 81% in rats.
authors.affiliation: Shanghai Institute for Biological Sciences , Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qisheng
authors.initials: Q
authors.lastname: Xin
authors.forename: Houxing
authors.initials: H
authors.lastname: Fan
authors.forename: Bin
authors.initials: B
authors.lastname: Guo
authors.forename: Huili
authors.initials: H
authors.lastname: He
authors.forename: Suo
authors.initials: S
authors.lastname: Gao
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Huang
authors.forename: Yushe
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D018360:Crystallography, X-Ray; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D005260:Female; D006094:Gram-Positive Bacteria / Q000187:drug effects; D000069349:Linezolid; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013203:Staphylococcal Infections / Q000188:drug therapy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D048588:Benzoxazines; D023303:Oxazolidinones; D000069349:Linezolid