Design and synthesis of simple macrocycles active against vancomycin-resistant enterococci (VRE).
16-membered meta,para-cyclophanes mimicking the vancomycin binding pocket (D-O-E ring) were designed and synthesized. The structural key features of these biaryl ether containing macrocycles are (1) the presence of beta-amino-alpha-hydroxy acid or alpha,beta-diamino acid as the C-terminal component of the cyclopeptide and (2) the presence of a hydrophobic chain or lipidated aminoglucose at the appropriate position. Cycloetherification by an intramolecular nucleophilic aromatic substitution reaction (S(N)Ar) is used as the key step for the construction of the macrocycle. The atropselectivity of this ring-closure reaction is found to be sensitive to the peptide backbone and chemoselective cyclization (phenol versus primary amine) is achievable. Glycosylation of phenol was realized with freshly prepared 3,4,6-tri-O-acetyl-2-N-lauroyl-2-amino-2-deoxy-alpha-D-glucopyranosyl bromide under phase-transfer conditions. Minimum inhibitory concentrations for all of the derivatives are measured by using a standard microdilution assay, and potent bioactivities against both sensitive and resistant strains are found for some of these compounds (MIC (minimum inhibitory concentration) = 4 microg mL(-1) against VRE). From these preliminary SAR studies, it was anticipated that both the presence of a hydrophobic substituent and an appropriate structure of the macrocycle were required for this series of compounds to be active against VRE.
Jia
Yanxing
Y
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France.
Ma
Nianchun
N
Liu
Zuosheng
Z
Bois-Choussy
Michèle
M
Gonzalez-Zamora
Eduardo
E
Malabarba
Adriano
A
Brunati
Cristina
C
Zhu
Jieping
J
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D016983:Enterococcus / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013211:Staphylococcus aureus / Q000187:drug effects; D020713:Vancomycin Resistance / Q000187:drug effects*
D000577:Amides; D000900:Anti-Bacterial Agents; D006571:Heterocyclic Compounds; D007202:Indicators and Reagents