Apfel C, Banner D W, Bur D, Dietz M, Hubschwerlen C, Locher H, Marlin F, Masciadri R, Pirson W, Stalder H
Discovery Chemistry, F. Hoffmann-La Roche Ltd., CH-4070 Basle, Switzerland.
J Med Chem. 2001 Jun 7;44(12):1847-52. doi: 10.1021/jm000352g.
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.
通过对弱结合筛选命中物（5-氯-2-氧代-1,4-二氢-2H-喹唑啉-3-基）乙酸酰肼（1）进行合理优化，获得了高效、选择性且结构新颖的大肠杆菌肽脱甲酰基酶（PDF）抑制剂。从与1络合的镍-PDF收集的三维结构信息表明，制备了两个系列的相关异羟肟酸类似物，即2-（2-氧代-1,4-二氢-2H-喹唑啉-3-基）-N-羟基乙酰胺（A）和2-（2,2-二氧代-1,4-二氢-2H-2λ(6)-苯并[1,2,6]噻二嗪-3-基）-N-羟基乙酰胺（B），其中鉴定出了高效的PDF抑制剂（37、42和48）。此外，从每个系列中选出的两种化合物，即36和41，对PDF的选择性优于包括基质金属蛋白酶在内的几种内切蛋白酶。然而，这些化合物仅表现出较弱的抗菌活性。
