Design and synthesis of macrocycles active against vancomycin-resistant enterococci (VRE): the interplay between d-Ala-d-Lac binding and hydrophobic effect |
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Authors: | Ma Nianchun Jia Yanxing Liu Zuosheng Gonzalez-Zamora Eduardo Bois-Choussy Michèle Malabarba Adriano Brunati Cristina Zhu Jieping |
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Affiliation: | Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France. |
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Abstract: | A modified vancomycin binding pocket (D-O-E ring) incorporating a CHNHCOR function at the AA4 position is designed and synthesized. Potent bioactivities against both sensitive- and resistant-strain are found for some of these compounds (MIC 4 microg/mL against VREF). From this preliminary SAR studies, it was speculated that the D-Ala-D-Ala binding was required for this series of compounds since the corresponding des-leucine derivative is inactive. The presence of long aliphatic chain was important for the desired activities and such hydrophobic effect is specific as no beneficial effect is observed when the same aliphatic chain was attached to the other part of the molecule. |
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