Design, synthesis and evaluation of the antibacterial enhancement activities of amino dihydroartemisinin derivatives.

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 themselves. 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.

• Authors: Chong Wu, Jian Liu, Xichun Pan, Wenying Xian, Bin Li, Wei Peng, Jingfang Wang, Dacheng Yang, Hong Zhou
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 18 Issue 6 Pg. 6866-82 (Jun 10 2013) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 23752470 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AcrB protein, E coli
• Anti-Bacterial Agents
• Artemisinins
• Escherichia coli Proteins
• Ligands
• Multidrug Resistance-Associated Proteins
• artenimol

Topics

• Anti-Bacterial Agents (pharmacology)
• Artemisinins (chemical synthesis, chemistry, pharmacology)
• Drug Design
• Drug Synergism
• Escherichia coli (drug effects, metabolism)
• Escherichia coli Proteins (chemistry, metabolism)
• Ligands
• Microbial Sensitivity Tests
• Molecular Conformation
• Molecular Docking Simulation
• Multidrug Resistance-Associated Proteins (chemistry, metabolism)
• Protein Binding