Importance of the structure of vancomycin binding pocket in designing compounds active against vancomycin-resistant enterococci (VRE).

16-Membered meta, para-cyclophanes mimicking the vancomycin binding pocket (D-O-E ring) are designed and synthesized. The structural features of these biaryl ether containing macrocycles are: a) the deletion of the carboxyl group of vancomycin's central amino acid (amino acid D); b) the elongation of the N-terminal; c) the presence of lipidated aminoglucose at the D-ring. Cycloetherification by way of an intramolecular nucleophilic aromatic substitution reaction (S(N)Ar) is used as a key step for the construction of the macrocycle. Minimum inhibitory concentrations for all of the derivatives are measured using a standard microdilution assay. Compounds 2a-2c and 3a-3c displayed weak activities against resistant strain Enterococcus faecalis L560 and were inactive against Enterococcus faecium resistant strain L2215.