Bioorganic & medicinal chemistry letters · 2013
Design, synthesis and structure-activity relationships of substituted oxazole-benzamide antibacterial inhibitors of FtsZ.
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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
Аннотация
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.