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N-alkyl urea hydroxamic acids as a new class of peptide deformylase inhibitors with antibacterial activity.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2002 Sep; Vol. 46 (9), pp. 2752-64. - Publication Year :
- 2002
-
Abstract
- Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P(1)' site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors with N-alkyl urea at the P(1)' site. Compounds with MICs of <or=4 micro g/ml against gram-positive and gram-negative pathogens, including Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, have been identified. The concentrations needed to inhibit 50% of enzyme activity (IC(50)s) for Escherichia coli Ni-PDF were <or=0.1 micro M, demonstrating the specificity of the inhibitors. In addition, these compounds were very selective for PDF, with IC(50)s of consistently >200 micro M for matrilysin and other mammalian metalloproteases. Structure-activity relationship analysis identified preferred substitutions resulting in improved potency and decreased cytotoxity. One of the compounds (VRC4307) was cocrystallized with PDF, and the enzyme-inhibitor structure was determined at a resolution of 1.7 A. This structural information indicated that the urea compounds adopt a binding position similar to that previously determined for succinate hydroxamates. Two compounds, VRC4232 and VRC4307, displayed in vivo efficacy in a mouse protection assay, with 50% protective doses of 30.8 and 17.9 mg/kg of body weight, respectively. These N-alkyl urea hydroxamic acids provide a starting point for identifying new PDF inhibitors that can serve as antimicrobial agents.
- Subjects :
- Animals
Bacteria drug effects
Biotransformation
Crystallography, X-Ray
DNA Primers
Drug Resistance
Drug Screening Assays, Antitumor
Escherichia coli metabolism
Female
Haemophilus influenzae drug effects
Haemophilus influenzae genetics
Humans
Hydroxamic Acids pharmacokinetics
In Vitro Techniques
Male
Mice
Microbial Sensitivity Tests
Microsomes, Liver metabolism
Molecular Conformation
Protease Inhibitors pharmacokinetics
Rats
Rats, Sprague-Dawley
Sepsis drug therapy
Sepsis microbiology
Streptococcus pneumoniae drug effects
Streptococcus pneumoniae genetics
Structure-Activity Relationship
Tumor Cells, Cultured
Urea chemical synthesis
Urea pharmacokinetics
Urea pharmacology
Amidohydrolases
Aminopeptidases antagonists & inhibitors
Hydroxamic Acids chemical synthesis
Hydroxamic Acids pharmacology
Protease Inhibitors chemical synthesis
Protease Inhibitors pharmacology
Urea analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0066-4804
- Volume :
- 46
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 12183225
- Full Text :
- https://doi.org/10.1128/AAC.46.9.2752-2764.2002