Solubility-Driven Optimization of (Pyridin-3-yl) Benzoxazinyl-oxazolidinones Leading to a Promising Antibacterial Agent
Solubility-Driven Optimization of (Pyridin-3-yl) Benzoxazinyl-oxazolidinones Leading to a Promising Antibacterial Agent
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(吡啶-3-基)苯并恶嗪基恶唑烷酮的溶解度驱动优化可产生有前景的抗菌剂
DOI：
10.1021/jm4000598
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发表时间：
2013-03-28
影响因子：
7.3
通讯作者：
Yang, Yushe
中科院分区：
文献类型：
--
作者：
Guo, Bin;Fan, Houxing;Yang, Yushe
描述了（吡啶-3-基）苯并恶嗪基-恶唑烷酮的溶解度驱动的结构修饰，这导致开发了一系列新的苯并恶嗪基-恶唑烷酮类似物，其对革兰氏阳性病原体具有高抗菌活性，包括对利奈唑胺耐药菌株和低hERG抑制。对于吡啶环上的各种取代基之间的构效关系（SAR）的趋势，相对较小的和非碱性的取代基是优选的空间要求或碱性取代基。在吡啶环上进行恶唑烷酮环取代，生成抗菌活性上级于咪唑烷酮环的类似物。溶解度提高了极性基团的掺入，特别是当化合物转化为它们的前药。在前药中，化合物85表现出优异的溶解性和良好的药代动力学特征。在MRSA全身感染模型中，化合物85显示出ED 50 = 5.00 mg/kg，效力比利奈唑胺好2倍。
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.