Shanghai Institute for Biological Sciences , Chinese Academy of Sciences, Shanghai, China.
J Med Chem. 2011 Nov 10;54(21):7493-502. doi: 10.1021/jm200614t. Epub 2011 Oct 12.
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.
设计并合成了一系列含有非芳杂环或芳基的新型苯并恶嗪基恶唑烷酮。研究了它们的体外和体内抗菌活性。大多数（3S，3aS）联芳基苯并恶嗪基恶唑烷酮对革兰氏阳性病原体表现出很强的活性。观察到 SAR 趋势；与其他 5 或 6 元芳基 C 环相比，吡啶 C 环更可取，而 B 环上的氟取代会生成活性降低的衍生物。还评估了吡啶环上各种取代基位置。所得化合物对耐唑烷酮的菌株表现出优异的活性。化合物 45 表现出优异的体外活性，对 MRSA 的 MIC 值为 0.25-0.5 μg/mL，对耐唑烷酮的菌株的活性比唑烷酮高 8-16 倍。在 MRSA 全身感染模型中，化合物 45 的 ED（50）<5.0 mg/kg，效力比唑烷酮高近 3 倍。该化合物还表现出优异的药代动力学特性，在大鼠中的半衰期超过 5 小时，口服生物利用度为 81%。
