School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
Eur J Med Chem. 2013 Jan;59:54-63. doi: 10.1016/j.ejmech.2012.10.054. Epub 2012 Nov 8.
A series of 9-O-(3-aryl-2-propargyl)oxime ketolides 8 was synthesized and evaluated for in vitro antibacterial activity. Among 8, 8b-8d, and 8h-8l displayed dramatically improved potency against inducibly MLS(B)-resistant and efflux-resistant pathogens as compared to clarithromycin and azithromycin. Especially, 8i (Ar=4-isoquinolyl) possessed an MIC of 0.064 μg/mL against constitutively MLS(B)-resistant Streptococcus pneumoniae, and MICs of 0.032-0.064 μg/mL against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus hominis. The analog 10 with a propyl linker was less effective than both the corresponding 8 and 9 containing propynyl and propenyl linkers. A docking study was performed to gain insight into the binding mode of series 8 and 9 and to rationalize the disparity found in the SAR of 8 and 9.
我们合成了一系列 9-O-(3-芳基-2-丙炔基)肟酮内酯 8，并评估了它们的体外抗菌活性。在 8、8b-8d 和 8h-8l 中，与克拉霉素和阿奇霉素相比，它们对诱导性 MLS(B)-耐药和外排耐药病原体的活性显著提高。特别是 8i（Ar=4-异喹啉基）对固有 MLS(B)-耐药肺炎链球菌的 MIC 为 0.064μg/mL，对耐甲氧西林金黄色葡萄球菌和耐甲氧西林人葡萄球菌的 MIC 为 0.032-0.064μg/mL。带有丙基连接子的类似物 10 的活性不如含有丙炔基和丙烯基连接子的相应 8 和 9 有效。我们进行了对接研究，以深入了解 8 和 9 系列的结合模式，并合理解释了 8 和 9 的 SAR 中的差异。
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