title: 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.
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.
authors.affiliation: Discovery Chemistry, F. Hoffmann-La Roche Ltd., CH-4070 Basle, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Apfel
authors.forename: D W
authors.initials: DW
authors.lastname: Banner
authors.forename: D
authors.initials: D
authors.lastname: Bur
authors.forename: M
authors.initials: M
authors.lastname: Dietz
authors.forename: C
authors.initials: C
authors.lastname: Hubschwerlen
authors.forename: H
authors.initials: H
authors.lastname: Locher
authors.forename: F
authors.initials: F
authors.lastname: Marlin
authors.forename: R
authors.initials: R
authors.lastname: Masciadri
authors.forename: W
authors.initials: W
authors.lastname: Pirson
authors.forename: H
authors.initials: H
authors.lastname: Stalder
mesh_terms: D000581:Amidohydrolases; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000302:isolation & purification; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004926:Escherichia coli / Q000201:enzymology*; D006801:Humans; D006860:Hydrogen Bonding; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D011799:Quinazolines; D013829:Thiadiazines; D000626:Aminopeptidases; D000581:Amidohydrolases; C084507:peptide deformylase