title: 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.affiliation: Department of Pharmacology, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Wu
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Xichun
authors.initials: X
authors.lastname: Pan
authors.forename: Wenying
authors.initials: W
authors.lastname: Xian
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.forename: Jingfang
authors.initials: J
authors.lastname: Wang
authors.forename: Dacheng
authors.initials: D
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D037621:Artemisinins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding
chemical_list: D000900:Anti-Bacterial Agents; D037621:Artemisinins; D029968:Escherichia coli Proteins; D008024:Ligands; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C083496:AcrB protein, E coli; C039060:artenimol