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.
Jia
Yanxing
Y
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur- Yvette Cedex, France. zhu@icsn.cnrs-gif.fr
Bois-Choussy
Michèle
M
Malabarba
Adriano
A
Brunati
Cristina
C
Zhu
Jieping
J
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical; D016983:Enterococcus / Q000187:drug effects*; D013293:Enterococcus faecalis / Q000187:drug effects; D016984:Enterococcus faecium / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D014640:Vancomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020713:Vancomycin Resistance
D000900:Anti-Bacterial Agents; D014640:Vancomycin