Flavonolignan and flavone inhibitors of a Staphylococcus aureus multidrug resistance pump:: Structure-activity relationships
Flavonolignan and flavone inhibitors of a Staphylococcus aureus multidrug resistance pump:: Structure-activity relationships
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DOI：
10.1021/jm0004190
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发表时间：
2001-01-18
影响因子：
7.3
通讯作者：
Lewis, K
中科院分区：
文献类型：
--
作者：
Guz, NR;Stermitz, FR;Lewis, K
尽管哺乳动物P-糖蛋白MDR外排泵抑制剂的构效关系（SAR）研究取得了一些进展，但几乎没有任何文献报道任何细菌外排泵抑制剂的SAR。事实上，只描述了其中的一些。我们发现了一种天然存在的金黄色葡萄球菌诺拉MDR泵的有效黄酮木脂素抑制剂，这为通过合成类似物评估SAR提供了结构基础。制备了几种黄酮木脂素，证明其具有比天然分离物5 '-甲氧基大风子苷-D更大的效力，而其他的显示出降低的效力。令人惊讶的是，一些简单的烷基化黄酮也是相当活跃的MDR泵抑制剂。测试的化合物之间的活性的变异性是足够的，使得至少一些SAR可以被假定，并与已知的P-糖蛋白进行比较。
Although some progress has been reported on structure-activity relationships (SARs) for inhibitors of mammalian P-glycoprotein MDR efflux pumps, there is almost nothing in the literature regarding SARs for inhibitors of any bacterial efflux pump. Indeed, only a few of these have been described. Our discovery of a potent naturally occurring flavonolignan inhibitor of the NorA MDR pump of Staphylococcus aureus provided a structural foundation upon which SARs could be assessed via synthetic analogues. Several flavonolignans were prepared which proved to have greater potency than the natural isolate, 5'-methoxyhydnocarpin-D, while others showed decreased potency. Surprisingly, some simple alkylated flavones also were quite active MDR pump inhibitors. Variability of activity among the compounds tested was sufficient so that at least some SARs could be postulated and compared with those known for P-glycoprotein.