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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.
Antimicrob Agents Chemother ; 57(1): 317-25, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23114779

ABSTRACT

The bacterial cell division protein FtsZ is an attractive target for small-molecule antibacterial drug discovery. Derivatives of 3-methoxybenzamide, including compound PC190723, have been reported to be potent and selective antistaphylococcal agents which exert their effects through the disruption of intracellular FtsZ function. Here, we report the further optimization of 3-methoxybenzamide derivatives towards a drug candidate. The in vitro and in vivo characterization of a more advanced lead compound, designated compound 1, is described. Compound 1 was potently antibacterial, with an average MIC of 0.12 µg/ml against all staphylococcal species, including methicillin- and multidrug-resistant Staphylococcus aureus and Staphylococcus epidermidis. Compound 1 inhibited an S. aureus strain carrying the G196A mutation in FtsZ, which confers resistance to PC190723. Like PC190723, compound 1 acted on whole bacterial cells by blocking cytokinesis. No interactions between compound 1 and a diverse panel of antibiotics were measured in checkerboard experiments. Compound 1 displayed suitable in vitro pharmaceutical properties and a favorable in vivo pharmacokinetic profile following intravenous and oral administration, with a calculated bioavailability of 82.0% in mice. Compound 1 demonstrated efficacy in a murine model of systemic S. aureus infection and caused a significant decrease in the bacterial load in the thigh infection model. A greater reduction in the number of S. aureus cells recovered from infected thighs, equivalent to 3.68 log units, than in those recovered from controls was achieved using a succinate prodrug of compound 1, which was designated compound 2. In summary, optimized derivatives of 3-methoxybenzamide may yield a first-in-class FtsZ inhibitor for the treatment of antibiotic-resistant staphylococcal infections.


Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Bacterial Proteins/antagonists & inhibitors , Benzamides/pharmacokinetics , Cytoskeletal Proteins/antagonists & inhibitors , Methicillin-Resistant Staphylococcus aureus/drug effects , Oxazoles/pharmacokinetics , Prodrugs/pharmacokinetics , Staphylococcal Infections/drug therapy , Staphylococcus epidermidis/drug effects , Succinates/pharmacokinetics , Administration, Oral , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/genetics , Benzamides/chemical synthesis , Benzamides/chemistry , Benzamides/pharmacology , Biological Availability , Colony Count, Microbial , Cytokinesis/drug effects , Cytoskeletal Proteins/genetics , Drug Resistance, Multiple, Bacterial , Female , Injections, Intravenous , Methicillin-Resistant Staphylococcus aureus/genetics , Methicillin-Resistant Staphylococcus aureus/growth & development , Mice , Microbial Sensitivity Tests , Mutation , Oxazoles/chemical synthesis , Oxazoles/pharmacology , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Staphylococcal Infections/microbiology , Staphylococcus epidermidis/growth & development , Succinates/chemical synthesis , Succinates/pharmacology , Succinic Acid/chemistry , Thigh/microbiology , Treatment Outcome
3.
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
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