title: Solubility-driven optimization of (pyridin-3-yl) benzoxazinyl-oxazolidinones leading to a promising antibacterial agent.
abstract: The solubility-driven structural modification of (pyridin-3-yl) benzoxazinyl-oxazolidinones is described, which resulted in the development of a new series of benzoxazinyl-oxazolidinone analogues with high antibacterial activity against Gram-positive pathogens, including that against linezolid-resistant strains and low hERG inhibition. With regard to structure-activity relationship (SAR) trends among the various substituents on the pyridyl ring, relatively small and nonbasic substituents were preferable to sterically demanding or basic substituents. Oxazolidinone ring substitution on the pyridyl ring generated analogues with antibacterial activity superior to imidazolidinone ring. Solubility was enhanced by the incorporation of polar groups, especially when compounds were converted to their prodrugs. Among the prodrugs, compound 85 exhibited excellent solubility and a good pharmacokinetic profile. In a MRSA systemic infection model, compound 85 displayed an ED50 = 5.00 mg/kg, a potency that is 2-fold better than that of linezolid.
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Bin
authors: B
authors: Guo
authors: Houxing
authors: H
authors: Fan
authors: Qisheng
authors: Q
authors: Xin
authors: Wenjing
authors: W
authors: Chu
authors: Hui
authors: H
authors: Wang
authors: Yanqin
authors: Y
authors: Huang
authors: Xiaoyan
authors: X
authors: Chen
authors: Yushe
authors: Y
authors: Yang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005260:Female; D051379:Mice; D008826:Microbial Sensitivity Tests; D023303:Oxazolidinones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012995:Solubility
chemical_list: D000900:Anti-Bacterial Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D023303:Oxazolidinones