title: Design and synthesis of macrocycles active against vancomycin-resistant enterococci (VRE): the interplay between d-Ala-d-Lac binding and hydrophobic effect.
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.
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Nianchun
authors.initials: N
authors.lastname: Ma
authors.forename: Yanxing
authors.initials: Y
authors.lastname: Jia
authors.forename: Zuosheng
authors.initials: Z
authors.lastname: Liu
authors.forename: Eduardo
authors.initials: E
authors.lastname: Gonzalez-Zamora
authors.forename: Michèle
authors.initials: M
authors.lastname: Bois-Choussy
authors.forename: Adriano
authors.initials: A
authors.lastname: Malabarba
authors.forename: Cristina
authors.initials: C
authors.lastname: Brunati
authors.forename: Jieping
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D004352:Drug Resistance, Microbial; D016983:Enterococcus / Q000187:drug effects*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D014640:Vancomycin
chemical_list: D000900:Anti-Bacterial Agents; D047028:Macrocyclic Compounds; D014640:Vancomycin