Design, synthesis and evaluation of the antibacterial enhancement activities of amino dihydroartemisinin derivatives.
Design, synthesis and evaluation of the antibacterial enhancement activities of amino dihydroartemisinin derivatives.
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DOI：
10.3390/molecules18066866
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发表时间：
2013-06-10
期刊：
影响因子：
--
通讯作者：
Zhou H
中科院分区：
文献类型：
--
作者：
Wu C;Liu J;Pan X;Xian W;Li B;Peng W;Wang J;Yang D;Zhou H
青蒿素（ART）及其衍生物青蒿琥酯（AS）、双氢青蒿素（DHA）是一组含有倍半萜内酯的药物，用于治疗疟疾。先前，AS被证明没有抗菌活性，但可以显著提高β-内酰胺类抗生素对大肠杆菌的抗菌活性。其中，分子对接实验表明，ART、AS和DHA能够很好地对接AcrB，尤其是DHA和AS；DHA和AS都有相同的对接姿势。AS与AcrB的亲和性似乎弱于DHA，而AS的琥珀酸尾巴像“虫子”一样可以很好地在binding pocket中延伸。模仿DHA的母核和AS的琥珀酸尾，设计合成了21个DHA衍生物4a-u。其中，有17种是新化合物。对大肠杆菌AG100A/pET28a-AcrB的协同作用表明，新结构的4k、41、4m、4n和4r虽然本身没有直接的抗菌活性，但与β-内酰胺类抗生素具有显著的协同作用。细菌生长试验显示，只有4k与氨苄西林或头孢呋辛联用才能在0 ~ 12 h内完全抑制细菌生长，说明4k的抗菌增强效果最好。综上所述，我们的研究结果为多重耐药大肠杆菌的抗菌活性增强剂提供了新的思路和几种候选化合物。
Artemisinin (ART) and its derivatives artesunate (AS), dihydroartemisinin (DHA) are a group of drugs containing a sesquiterpene lactone used to treat malaria. Previously, AS was shown to not have antibacterial activity but to significantly increase the antibacterial activities of β-lactam antibiotics against E. coli. Herein, molecular docking experiments showed that ART, AS and DHA could dock into AcrB very well, especially DHA and AS; both DHA and AS had the same docking pose. The affinity between AS and AcrB seemed weaker than that of DHA, while the succinate tail of AS, which was like a “bug”, could extend in the binding pocket very well. Imitating the parent nucleus of DHA and the succinate tail of AS, twenty-one DHA derivatives 4a–u were designed and synthesized. Among them, seventeen were new compounds. The synergistic effects against E. coli AG100A/pET28a-AcrB showed among the new structures 4k, 4l, 4m, 4n, and 4r exhibited significant synergism with β-lactam antibiotics although they had no direct antibacterial activities themelves. The bacterial growth assay showed that only 4k in combination with ampicillin or cefuroxime could totally inhibit bacterial growth from 0 to 12 h, demonstrating that 4k had the best antibacterial enhancement effect. In conclusion, our results provided a new idea and several candidate compounds for antibacterial activity enhancers against multidrug resistant E. coli.
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影响因子：
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影响因子：
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