1. 2-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)- and 2-(2,2-dioxo-1,4-dihydro-2H-2lambda6-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxy-acetamides as potent and selective peptide deformylase inhibitors.
- Author
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Apfel C, Banner DW, Bur D, Dietz M, Hubschwerlen C, Locher H, Marlin F, Masciadri R, Pirson W, and Stalder H
- Subjects
- Aminopeptidases chemistry, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Bacteria drug effects, Bacteria isolation & purification, Binding Sites, Crystallography, X-Ray, Drug Design, Humans, Hydrogen Bonding, Hydroxamic Acids chemistry, Hydroxamic Acids pharmacology, Microbial Sensitivity Tests, Models, Molecular, Molecular Conformation, Protease Inhibitors chemistry, Protease Inhibitors pharmacology, Quinazolines chemistry, Quinazolines pharmacology, Thiadiazines chemistry, Thiadiazines pharmacology, Amidohydrolases, Aminopeptidases antagonists & inhibitors, Anti-Bacterial Agents chemical synthesis, Escherichia coli enzymology, Hydroxamic Acids chemical synthesis, Protease Inhibitors chemical synthesis, Quinazolines chemical synthesis, Thiadiazines chemical synthesis
- Abstract
Potent, selective, and structurally new inhibitors of the Fe(II) enzyme Escherichia coli peptide deformylase (PDF) were obtained by rational optimization of the weakly binding screening hit (5-chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid hydrazide (1). Three-dimensional structural information, gathered from Ni-PDF complexed with 1, suggested the preparation of two series of related hydroxamic acid analogues, 2-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-N-hydroxy-acetamides (A) and 2-(2,2-dioxo-1,4-dihydro-2H-2lambda(6)-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxy-acetamides (B), among which potent PDF inhibitors (37, 42, and 48) were identified. Moreover, two selected compounds, one from each series, 36 and 41, showed good selectivity for PDF over several endoproteases including matrix metalloproteases. However, these compounds showed only weak antibacterial activity.
- Published
- 2001
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