Synthesis and Evaluation of Selected Key Methyl Ether Derivatives of Vancomycin Aglycon

• Published in: Journal of medicinal chemistry 2010-10, Vol.53 (19), p.7229-7235
• Main Authors: Crane, Christine M, Pierce, Joshua G, Leung, Siegfried S. F, Tirado-Rives, Julian, Jorgensen, William L, Boger, Dale L
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Drug Resistance, Bacterial; Enterococcus faecalis - drug effects; Hydrophobic and Hydrophilic Interactions; Methyl Ethers - chemical synthesis; Methyl Ethers - pharmacology; Microbial Sensitivity Tests; Peptidoglycan - chemistry; Staphylococcus aureus - drug effects; Stereoisomerism; Structure-Activity Relationship; Thermodynamics; Vancomycin - analogs & derivatives; Vancomycin - chemical synthesis; Vancomycin - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm100946e

A select series of methyl ether derivatives of vancomcyin aglycon were prepared and examined for antimicrobial activity against vancomycin-sensitive Staphylococcus aureus and vancomycin-resistant Enterococci faecalis as well as their binding affinity for d-Ala-d-Ala and d-Ala-d-Lac. The intent of the study was to elucidate the role selected key methyl groups may play in the improvement of the in vitro antimicrobial profile of the tetra methyl ether derivative of vancomycin aglycon against vancomycin-resistant Enterococci faecalis previously reported. In these studies, methodology for selective derivatization of the A-, B-, and D-ring was developed that defines the relative reactivity of the four phenols of vancomycin aglycon, providing a foundation for future efforts for site-directed modification of the vancomycin aglycon core.