Synthesis and Evaluation of Vancomycin Aglycon Analogues

Download or read book Synthesis and Evaluation of Vancomycin Aglycon Analogues written by Robert C. James and published by . This book was released on 2012 with total page 258 pages. Available in PDF, EPUB and Kindle. Book excerpt: The synthesis and evaluation of vancomycin aglycon, vancomycin aglycon, and a series of related vancomycin aglycon residue 4 substituted analogues is discussed. The synthetic approach not only permited access to vancomycin aglycon, but it also allows late-stage access to related residue 4 derivatives, alternative access to vancomycin aglycon from a common late-stage intermediate, and provides authentic residue 4 thioamide and amidine derivatives of the vancomycin aglycon that will facilitate ongoing efforts on their semisynthetic preparation. A key series of vancomycin aglycon residue 4 substituted amidines were prepared and their interaction with model ligands of peptidoglycan precursors was explored to clarify the nature of this interaction and the resulting impact on antimicrobial properties. The synthetically redesigned analogue, vancomycin aglycon, exhibited the dual binding to D-Ala-D-Ala and D-Ala-D-Lac needed to reinstate activity against vancomycin-resistant bacteria. Its binding to a model D-Ala- D-Ala ligand was found to be only 2-fold less than vancomycin aglycon and this affinity was maintained with a model D-Ala- D-Lac ligand, representing a 600-fold increase relative to vancomycin aglycon. Accurately reflecting these binding characteristics, it exhibited potent antimicrobial activity against vancomycin-resistant bacteria. Thus a complimentary single atom exchange in the vancomycin core structure to counter the single atom exchange in the cell wall precursors of resistant bacteria reinstated potent antimicrobial activity and charts a rational path forward for the development of antibiotics for the treatment of vancomycin-resistant bacterial infections.