Design, synthesis and structure-activity relationships of substituted oxazole-benzamide antibacterial inhibitors of FtsZ.
Basic Information
ID: ALA3098047
Journal: Bioorg Med Chem Lett
Title: Design, synthesis and structure-activity relationships of substituted oxazole-benzamide antibacterial inhibitors of FtsZ.
Authors: Stokes NR, Baker N, Bennett JM, Chauhan PK, Collins I, Davies DT, Gavade M, Kumar D, Lancett P, Macdonald R, Macleod L, Mahajan A, Mitchell JP, Nayal N, Nayal YN, Pitt GR, Singh M, Yadav A, Srivastava A, Czaplewski LG, Haydon DJ.
Abstract: The design, synthesis and structure-activity relationships of a series of oxazole-benzamide inhibitors of the essential bacterial cell division protein FtsZ are described. Compounds had potent anti-staphylococcal activity and inhibited the cytokinesis of the clinically-significant bacterial pathogen Staphylococcus aureus. Selected analogues possessing a 5-halo oxazole also inhibited a strain of S. aureus harbouring the glycine-to-alanine amino acid substitution at residue 196 of FtsZ which conferred resistance to previously reported inhibitors in the series. Substitutions to the pseudo-benzylic carbon of the scaffold improved the pharmacokinetic properties by increasing metabolic stability and provided a mechanism for creating pro-drugs. Combining multiple substitutions based on the findings reported in this study has provided small-molecule inhibitors of FtsZ with enhanced in vitro and in vivo antibacterial efficacy.
CiteXplore: 24287381
DOI: 10.1016/j.bmcl.2013.11.002
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