Solubility-Driven Optimization of (Pyridin-3-yl) Benzoxazinyl-oxazolidinones Leading to a Promising Antibacterial Agent

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-resis...

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Published inJournal of medicinal chemistry Vol. 56; no. 6; pp. 2642 - 2650
Main Authors Guo, Bin, Fan, Houxing, Xin, Qisheng, Chu, Wenjing, Wang, Hui, Huang, Yanqin, Chen, Xiaoyan, Yang, Yushe
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 28.03.2013
Amer Chemical Soc
Subjects
Animals
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacokinetics
Anti-Bacterial Agents - pharmacology
Bacteria - drug effects
Chemistry, Medicinal
Drug Design
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels - antagonists & inhibitors
Female
Life Sciences & Biomedicine
Mice
Microbial Sensitivity Tests
Oxazolidinones - chemistry
Oxazolidinones - pharmacokinetics
Oxazolidinones - pharmacology
Pharmacology & Pharmacy
Science & Technology
Solubility
RESISTANCE
AMERICA
STAPHYLOCOCCUS-AUREUS
INFECTIOUS-DISEASES SOCIETY
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Summary: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.
Bibliography:ObjectType-Article-1
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content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/jm4000598