利奈唑胺-黄酮杂合体的合成与抗菌活性研究

Synthesis and antibacterial activity evaluation of a linezolid-flavonoid hybrid

目的针对利奈唑胺日益严重的细菌耐药问题,将具有外排泵抑制作用的黄酮骨架引入利奈唑胺分子中,以提高抗耐药菌活性。方法通过黄酮的氧烷基化反应,连接臂酯基的选择性水解,TBTU存在下的缩合反应,得到黄酮-利奈唑胺杂合体5;采用MTT法测定其抗菌活性,采用荧光分光光度法测定其外排率,用SYBYL软件研究5与靶点可能的结合模式。结果化合物5抗金黄色葡萄球菌MIC_(50)为0.39μg/m L,活性是利奈唑胺的近2倍;金黄色葡萄球菌对化合物5的外排率(13.1%)远低于其母体化合物利奈唑胺(49.0%);化合物5和利奈唑胺具有相同的靶点结合模式。结论化合物5对革兰阳性和阴性菌均具有优良的抗菌活性;对核糖体具有高亲和性;对外排泵具有显著抑制作用。

Objective To combat the linezolid resistant bacterial strains, a novel hybrid of linezolid-flavonoid （5） was designed by the introduction of an efflux pump inhibitor to the linezolid core through a linker for the improvement of the potency against drug-resistant microorganism. Methods The linker was introduced by O-alkylation of a flavone, which was selectively hydrolyzed to the corresponding acid leaving an intact C-ring of flavonoid through control of pH in a range of 9.0-10.0. Compound 5 was given by condensation of the resulted acid with deacetyl linezolid in the presence of TBTU. Evaluation of antibacterial potency was performed by MTT method, and compound accumulations in cell were determined by fluorospectrophotometry. Molecular docking was achieved in the SYBYL environment. Results Compound 5 showed MIC50 of 0.39μg/mL against Staphylococcus aureus, about a 2-fold more potent than linezolid. Staphylococcus aureus showed efflux rate of 13.1% to compound 5, much lower than that to linezolid （49.0%）. Compound 5 also targets the ribosome as linezolid does. Conclusion Compound 5 showed excellent potency with expanded antibacterial spectrum against both Gram-positive and Gram-negative bacteria. The excellent potency of compound 5 may be caused by the inhibition to efflux pumps and high affinity to the ribosomes.