- Design, synthesis and structure-activity relationships of substituted oxazole-benzamide antibacterial inhibitors of FtsZ
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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.
- Stokes, Neil R.,Baker, Nicola,Bennett, James M.,Chauhan, Pramod K.,Collins, Ian,Davies, David T.,Gavade, Maruti,Kumar, Dushyant,Lancett, Paul,Macdonald, Rebecca,Macleod, Leanne,Mahajan, Anu,Mitchell, Jeffrey P.,Nayal, Narendra,Nayal, Yashodanand Nandan,Pitt, Gary R.W.,Singh, Mahipal,Yadav, Anju,Srivastava, Anil,Czaplewski, Lloyd G.,Haydon, David J.
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p. 353 - 359
(2014/01/17)
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- Design, synthesis and structure-activity relationships of substituted oxazole-benzamide antibacterial inhibitors of FtsZ
-
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.
- Stokes, Neil R.,Baker, Nicola,Bennett, James M.,Chauhan, Pramod K.,Collins, Ian,Davies, David T.,Gavade, Maruti,Kumar, Dushyant,Lancett, Paul,Macdonald, Rebecca,MaCleod, Leanne,Mahajan, Anu,Mitchell, Jeffrey P.,Nayal, Narendra,Nayal, Yashodanand Nandan,Pitt, Gary R.W.,Singh, Mahipal,Yadav, Anju,Srivastava, Anil,Czaplewski, Lloyd G.,Haydon, David J.
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p. 353 - 359
(2015/09/08)
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- AROMATIC AMIDES AND USES THEREOF
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The present invention provides compounds of Formula (I): and salts, racemates, isomers, diastereoisomers, enantiomers, hydrates, solvates, N-oxides, pharmaceutically acceptable derivatives or prodrugs thereof. Also provided the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture.
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