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1.
Bioorg Med Chem Lett ; 24(1): 353-9, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24287381

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.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Benzamides/pharmacology , Cytoskeletal Proteins/antagonists & inhibitors , Drug Design , Oxazoles/pharmacology , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Benzamides/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Oxazoles/chemistry , Staphylococcus aureus/chemistry , Structure-Activity Relationship
2.
J Med Chem ; 53(10): 3927-36, 2010 May 27.
Article in English | MEDLINE | ID: mdl-20426423

ABSTRACT

3-Methoxybenzamide (1) is a weak inhibitor of the essential bacterial cell division protein FtsZ. Alkyl derivatives of 1 are potent antistaphylococcal compounds with suboptimal drug-like properties. Exploration of the structure-activity relationships of analogues of these inhibitors led to the identification of potent antistaphylococcal compounds with improved pharmaceutical properties.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , Cytoskeletal Proteins/antagonists & inhibitors , Pyridines/chemical synthesis , Staphylococcus aureus/drug effects , Thiazoles/chemical synthesis , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Biological Availability , Blood Proteins/metabolism , Caco-2 Cells , Cell Division/drug effects , Cell Membrane Permeability , Hepatocytes/metabolism , Humans , Mice , Microbial Sensitivity Tests , Models, Molecular , Protein Binding , Pyridines/chemistry , Pyridines/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/cytology , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology
3.
Science ; 321(5896): 1673-5, 2008 Sep 19.
Article in English | MEDLINE | ID: mdl-18801997

ABSTRACT

FtsZ is an essential bacterial guanosine triphosphatase and homolog of mammalian beta-tubulin that polymerizes and assembles into a ring to initiate cell division. We have created a class of small synthetic antibacterials, exemplified by PC190723, which inhibits FtsZ and prevents cell division. PC190723 has potent and selective in vitro bactericidal activity against staphylococci, including methicillin- and multi-drug-resistant Staphylococcus aureus. The putative inhibitor-binding site of PC190723 was mapped to a region of FtsZ that is analogous to the Taxol-binding site of tubulin. PC190723 was efficacious in an in vivo model of infection, curing mice infected with a lethal dose of S. aureus. The data validate FtsZ as a target for antibacterial intervention and identify PC190723 as suitable for optimization into a new anti-staphylococcal therapy.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacillus subtilis/drug effects , Bacterial Proteins/antagonists & inhibitors , Cytoskeletal Proteins/antagonists & inhibitors , Pyridines/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Thiazoles/pharmacology , Amino Acid Sequence , Animals , Anti-Bacterial Agents/therapeutic use , Bacillus subtilis/chemistry , Bacillus subtilis/genetics , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Binding Sites , Cell Division/drug effects , Crystallography, X-Ray , Cytoskeletal Proteins/chemistry , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Drug Resistance, Bacterial/genetics , Drug Resistance, Multiple, Bacterial , Ligands , Methicillin Resistance , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Sequence Data , Mutation , Protein Conformation , Pyridines/chemistry , Pyridines/metabolism , Pyridines/therapeutic use , Staphylococcus aureus/chemistry , Thiazoles/chemistry , Thiazoles/metabolism , Thiazoles/therapeutic use , Tubulin/chemistry , Tubulin/metabolism
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