Design, Synthesis, and Antibacterial Activity of Demethylvancomycin Analogues against Drug‐Resistant Bacteria. Issue 6 (10th April 2013)

• Record Type: Journal Article
• Authors: Chang, Jun; Zhang, Si‐Ji; Jiang, Yong‐Wei; Xu, Liang; Yu, Jian‐Ming; Zhou, Wen‐Jiang; Sun, Xun
• Is Part Of: ChemMedChem. Volume 8:Issue 6(2013:Jun.)
• Page Start: 976
• Page End: 984
• Publication Date: 2013-04-10
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201300011
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 <italic>Staphylococcus aureus</italic> (MRSA), gentamicin‐resistant <italic>Enterococcus faecalis</italic> (GRE), methicillin‐resistant <italic>Streptococcus pneumoniae</italic> (MRS), and vancomycin‐resistant <italic>Enterococcus faecalis</italic> (VRE) were evaluated. One of the compounds, <italic>N</italic>‐(6‐phenylheptyl)demethylvancomycin (<bold>12 a</bold>), was found to exhibit more potent antibacterial activity than vancomycin and demethylvancomycin. Compound <bold>12 a</bold> 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 <bold>12 a</bold> 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 <bold>12 a</bold> is a promising antibacterial drug candidate for further preclinical evaluation.</p> </abstract>