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: antibiotics -- demethylvancomycin -- drug resistance -- structure–activity relationships -- synthesis design; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201300011
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Compound12 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, compound12 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 that12 a is a promising antibacterial drug candidate for further preclinical evaluation. Abstract : The best of five: N‐Substituted demethylvancomycin derivatives were rationally designed and synthesized by using a structure‐based approach. One of the compounds was found to exhibit more potent antibacterial activity against drug‐resistant bacteria than vancomycin or demethylvancomycin, suggesting its promise as an antibacterial drug candidate.