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.

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.

Identification of synthetic compounds active against VRE: the role of the lipidated aminoglucose and the structure of glycopeptide binding pocket.

A modified vancomycin binding pocket (D-O-E ring) incorporating an alpha-hydroxy-beta-amino acid at the AA4 position is designed and synthesized. Some of these compounds display potent bioactivities against both sensitive- and resistant-strains (8 microg/ml against VREF). Both the lipidated aminoglucose and the structure of the 16-membered macrocycle are found to be important for the anti-VRE activities.

Synthesis of beta-amino-alpha-hydroxy esters and beta-amino-alpha-azido ester by Sharpless asymmetric aminohydroxylation, byproducts analysis.

[reaction: see text] Synthesis of enantiomerically pure beta-amino-alpha-hydroxy esters (1, 2) and beta-amino-alpha-azido ester (3) using Sharpless AA as a key step is described. A hitherto unreported side reaction, the oxidation of the beta-hydroxy-alpha-amino ester (5) into the alpha,alpha-di-tert-butyloxycarbamoyl-beta-ketoester (8) under AA conditions, is documented.

Human pharmacokinetics and rationale for once-weekly dosing of dalbavancin, a semi-synthetic glycopeptide.

The selection of a novel weekly dalbavancin dosage regimen was based on pharmacokinetic and pharmacodynamic data from humans and an animal model of infection. The results from the granuloma pouch model of infection suggested that dalbavancin concentrations >/=5 mg/L are necessary for extended in vivo activity. Serum bactericidal activity assessments demonstrated that dalbavancin serum concentrations of approximately 20 mg/L were bactericidal upon two-fold dilution.

Origin, structure, and activity in vitro and in vivo of dalbavancin.

Dalbavancin is a novel semi-synthetic lipoglycopeptide that was designed to improve upon the natural glycopeptides currently available, vancomycin and teicoplanin. Chemical modification of natural glycopeptides has produced compounds with more potent antimicrobial activity and longer t(1/2), while maintaining an excellent safety profile. Dalbavancin, prepared from a teicoplanin-like glycopeptide, has better activity, in vitro and in animal infection models, than vancomycin and teicoplanin.

Design and synthesis of macrocycles active against vancomycin-resistant enterococci (VRE): the interplay between d-Ala-d-Lac binding and hydrophobic effect.

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.