期刊
CHEMMEDCHEM
卷 8, 期 6, 页码 976-984出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201300011
关键词
antibiotics; demethylvancomycin; drug resistance; structureactivity relationships; synthesis design
资金
- National Natural Science Foundation of China [81172920]
- National Science and Technology Major Project of China [2009ZXJ09004-090, 2012ZX09J12108-05C]
- National Basic Research Program of China (973 Program) [2010CB912603]
Five novel N-substituted demethylvancomycin derivatives were rationally designed and synthesized by using a structure-based approach. The invitro antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA), gentamicin-resistant Enterococcus faecalis (GRE), methicillin-resistant Streptococcus pneumoniae (MRS), and vancomycin-resistant Enterococcus faecalis (VRE) were evaluated. One of the compounds, N-(6-phenylheptyl)demethylvancomycin (12a), was found to exhibit more potent antibacterial activity than vancomycin and demethylvancomycin. Compound 12a was also found to be approximate to 18-fold more efficacious than vancomycin against MRSA; however, the two compounds were found to have similar efficacy against MRS. Furthermore, compound 12a exhibited a favorable pharmacokinetic profile with a half-life of 5.11 +/- 0.52h, which is longer than that of vancomycin (4.3 +/- 1.9h). These results suggest that 12a is a promising antibacterial drug candidate for further preclinical evaluation.
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