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Design, Synthesis and Evaluation of the Antibacterial Enhancement Activities of Amino Dihydroartemisinin Derivatives
Department of Pharmacology, College of Pharmacy, Third Military Medical University, Chongqing 400038, China
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
* Author to whom correspondence should be addressed.
Received: 14 May 2013; in revised form: 29 May 2013 / Accepted: 30 May 2013 / Published: 10 June 2013
Abstract: 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.
Keywords: dihydroartemisinin; derivatives; antibiotic resistance; antibacterial activity; synergistic effect; β-lactam antibiotic
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MDPI and ACS Style
Wu, C.; Liu, J.; Pan, X.; Xian, W.; Li, B.; Peng, W.; Wang, J.; Yang, D.; Zhou, H. Design, Synthesis and Evaluation of the Antibacterial Enhancement Activities of Amino Dihydroartemisinin Derivatives. Molecules 2013, 18, 6866-6882.
Wu C, Liu J, Pan X, Xian W, Li B, Peng W, Wang J, Yang D, Zhou H. Design, Synthesis and Evaluation of the Antibacterial Enhancement Activities of Amino Dihydroartemisinin Derivatives. Molecules. 2013; 18(6):6866-6882.
Wu, Chong; Liu, Jian; Pan, Xichun; Xian, Wenying; Li, Bin; Peng, Wei; Wang, Jingfang; Yang, Dacheng; Zhou, Hong. 2013. "Design, Synthesis and Evaluation of the Antibacterial Enhancement Activities of Amino Dihydroartemisinin Derivatives." Molecules 18, no. 6: 6866-6882.