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2-(2-Oxo-1,4-dihydro-2 H -quinazolin-3-yl)- and 2-(2,2-Dioxo-1,4-dihydro-2 H -2λ 6 -benzo[1,2,6]thiadiazin-3-yl)- N -hydroxy-acetamides as Potent and Selective Peptide Deformylase Inhibitors

2001; American Chemical Society; Volume: 44; Issue: 12 Linguagem: Inglês

10.1021/jm000352g

1520-4804

Christian Apfel, David W. Banner, Daniel Bur, Michel Dietz, Christian Hubschwerlen, Hans H. Locher, Frédéric Marlin, Raffaello Masciadri, Wolfgang Pirson, Henri Stalder,

Cancer-related gene regulation

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.