Infoscience

Journal article

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 contg. 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 intramol. nucleophilic arom. substitution reaction (SNAr) 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 vs. primary amine) is achievable. Glycosylation of phenol was realized with freshly prepd. 3,4,6-tri-O-acetyl-2-N-lauroyl-2-amino-2-deoxy-alpha -D-glucopyranosyl bromide under phase-transfer conditions. Min. inhibitory concns. for all of the derivs. are measured by using a std. microdilution assay, and potent bioactivities against both sensitive and resistant strains are found for some of these compds. [MIC (min. inhibitory concn.) = 4 micro g 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 compds. to be active against VRE. [on SciFinder (R)]

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