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

1
Department of Pharmacology, College of Pharmacy, Third Military Medical University, Chongqing 400038, China
2
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
3
Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
*
Author to whom correspondence should be addressed.
Molecules 2013, 18(6), 6866-6882; https://doi.org/10.3390/molecules18066866
Received: 14 May 2013 / Revised: 29 May 2013 / Accepted: 30 May 2013 / Published: 10 June 2013
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 4au 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. View Full-Text
Keywords: dihydroartemisinin; derivatives; antibiotic resistance; antibacterial activity; synergistic effect; β-lactam antibiotic dihydroartemisinin; derivatives; antibiotic resistance; antibacterial activity; synergistic effect; β-lactam antibiotic
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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.

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