title: Design, synthesis, and antibacterial activity of demethylvancomycin analogues against drug-resistant bacteria.
abstract: Five novel N-substituted demethylvancomycin derivatives were rationally designed and synthesized by using a structure-based approach. The in vitro 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 (12 a), was found to exhibit more potent antibacterial activity than vancomycin and demethylvancomycin. Compound 12 a was also found to be ~18-fold more efficacious than vancomycin against MRSA; however, the two compounds were found to have similar efficacy against MRS. Furthermore, compound 12 a exhibited a favorable pharmacokinetic profile with a half-life of 5.11±0.52 h, which is longer than that of vancomycin (4.3±1.9 h). These results suggest that 12 a is a promising antibacterial drug candidate for further preclinical evaluation.
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chang
authors.forename: Si-Ji
authors.initials: SJ
authors.lastname: Zhang
authors.forename: Yong-Wei
authors.initials: YW
authors.lastname: Jiang
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Yu
authors.forename: Wen-Jiang
authors.initials: WJ
authors.lastname: Zhou
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D013293:Enterococcus faecalis / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin