Department of Chemistry, Wesleyan University, Middletown, CT 06459, USA.
Department of Chemistry, Wesleyan University, Middletown, CT 06459, USA.
Bioorg Med Chem. 2019 Apr 1;27(7):1430-1436. doi: 10.1016/j.bmc.2019.02.023. Epub 2019 Feb 12.
Class C β-lactamases have previously been shown to be efficiently inactivated by O-aryloxycarbonyl hydroxamates. O-Phenoxycarbonyl-N-benzyloxycarbonylhydroxylamine (1) and O-phenoxycarbonyl-N-(R)-[(4-amino-4-carboxy-1-butyl)oxycarbonyl]hydroxylamine (2), for example, were found to be effective inactivators. The present paper describes a structure-activity study of these molecules to better define the important structural elements for high inhibitory activity. The results show that a well-positioned hydrophobic element (which may interact with the Tyr221 residue of the enzyme) and a negatively charged element, e.g. a carboxylate group (which may interact with Arg204), are required for high reactivity with the enzyme. The new compounds were found to inactivate by forming a carbonyl cross-linked enzyme (probably Ser64OCONHLys 315) as for 1 rather than the inert hydroxamoyl derivative observed with 2.
C 类 β-内酰胺酶先前已被证明可被 O-芳氧基羰基羟胺有效地失活。例如，O-苯氧基羰基-N-苄氧羰基羟胺（1）和 O-苯氧基羰基-N-[(4-氨基-4-羧基-1-丁基）氧羰基]羟胺（2）被发现是有效的失活剂。本文描述了这些分子的构效关系研究，以更好地确定高抑制活性的重要结构要素。结果表明，需要一个位置良好的疏水性元件（可能与酶的 Tyr221 残基相互作用）和一个带负电荷的元件，例如羧酸盐基团（可能与 Arg204 相互作用），才能与酶具有高反应性。与 2 不同，新化合物通过形成羰基交联酶（可能是 Ser64OCONHLys315）而不是与 1 观察到的惰性羟氨酰衍生物来失活。
