Design, Synthesis and Evaluation of the Antibacterial Enhancement Activities of Amino Dihydroartemisinin Derivatives

Molecules

Chong Wu²  Jian Liu³  Xichun Pan²  Wenying Xian²  Bin Li²  Wei Peng²  Jingfang Wang¹  Dacheng Yang³ 

[1] Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China;Department of Pharmacology, College of Pharmacy, Third Military Medical University, Chongqing 400038, China;School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China

关键词: dihydroartemisinin;    derivatives;    antibiotic resistance;    antibacterial activity;    synergistic effect;    β-lactam antibiotic;   

DOI  :  10.3390/molecules18066866

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.