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Bioorg Med Chem Lett. 2014 Jan 1;24(1):353-9. doi: 10.1016/j.bmcl.2013.11.002. Epub 2013 Nov 13.

Design, synthesis and structure-activity relationships of substituted oxazole-benzamide antibacterial inhibitors of FtsZ.

Author information

  • 1Biota Europe Ltd, Begbroke Science Park, Oxfordshire OX5 1PF, United Kingdom.
  • 2Jubilant Chemsys Ltd, B-34, Sector-58, Noida 201301, India.
  • 3Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, VIC 3168, Australia.
  • 4Biota Europe Ltd, Begbroke Science Park, Oxfordshire OX5 1PF, United Kingdom. Electronic address: d.haydon@biota.com.au.

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.

Copyright © 2013 Elsevier Ltd. All rights reserved.

KEYWORDS:

3-Methoxybenzamide; Antibacterial; Cell division; FtsZ; MRSA

PMID:
24287381
[PubMed - indexed for MEDLINE]
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