2-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)- and 2-(2,2-dioxo-1,4-dihydro-2H-2 lambda(6)-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxy-acetamides as potent andselective peptide deformylase inhibitors

Potent, selective, and structurally new inhibitors of the Fe(II) enzyme Esc herichia coli peptide deformylase (PDF) were obtained by rational optimizat ion of the weakly binding screening hit (5-chloro-2-oxo-1,4-dihydro-2H-quin azolin-3-yl)-acetic acid hydrazide (1). Three-dimensional structural inform ation, 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-qu inazolin-3-yl)hydroxy-acetamides (A) and 2-(2,2-dioxo-1,4-dihydro-2H-2 lamb da (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 selec ted 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.