Structure-activity relationship of 6-methylidene penems bearing tricyclic heterocycles as broad-spectrum beta-lactamase inhibitors: crystallographic structures show unexpected binding of 1,4-thiazepine intermediates.
Structure-activity relationship of 6-methylidene penems bearing tricyclic heterocycles as broad-spectrum beta-lactamase inhibitors: crystallographic structures show unexpected binding of 1,4-thiazepine intermediates.
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带有三环杂环的 6-亚甲基青霉烯作为广谱 β-内酰胺酶抑制剂的结构-活性关系：晶体结构显示出意外的 1,4-硫氮杂卓中间体结合。
DOI：
10.1021/jm049680x
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Knox,JamesR
中科院分区：
文献类型：
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作者：
Venkatesan,AranapakamM;Gu,Yansong;DosSantos,Osvaldo;Abe,Takao;Agarwal,Atul;Yang,Youjun;Petersen,PeterJ;Weiss,WilliamJ;Mansour,TarekS;Nukaga,Michiyoshi;Hujer,AndreaM;Bonomo,RobertA;Knox,JamesR
描述了一系列七种三环 6-亚甲基青霉烯作为新型 A 类和 C 类丝氨酸 β-内酰胺酶抑制剂的设计和合成。这些化合物被证明是 TEM-1 和 AmpC β-内酰胺酶的非常有效的抑制剂，而对 B 类金属-β-内酰胺酶 CcrA 的抑制剂效果较差。与哌拉西林结合，它们的体外活性增强了来自各种细菌的所有 C 类耐药菌株的敏感性。 17 与 A 类 SHV-1 和 C 类 GC1 酶的丝氨酸结合反应中间体的晶体结构已分别确定为分辨率为 2.0 和 1.4 Å，并精炼至 R 因子等于 0.163 和 0.145。在两种 β-内酰胺酶中，均形成七元 1,4-硫氮杂环。环中的立体C7原子在SHV-1中间体中具有R构型，并且在GC1中间体中具有R构型和S构型。在这两种配合物中，三环 C7 取代基和酪氨酸侧链之间的疏水堆积相互作用占主导地位，而不是 C3 羧酸基团的静电或氢键键合。 1,4-硫氮杂环结构的形成是基于α7-内三环化而提出的。
The design and synthesis of a series of seven tricyclic 6-methylidene penems as novel class A and C serine β-lactamase inhibitors is described. These compounds proved to be very potent inhibitors of the TEM-1 and AmpC β-lactamases and less so against the class B metallo-β-lactamase CcrA. In combination with piperacillin, their in vitro activities enhanced susceptibility of all class C resistant strains from various bacteria. Crystallographic structures of a serine-bound reaction intermediate of17with the class A SHV-1 and class C GC1 enzymes have been established to resolutions of 2.0 and 1.4 Å, respectively, and refined toR-factors equal 0.163 and 0.145. In both β-lactamases, a seven-membered 1,4-thiazepine ring has formed. The stereogenic C7 atom in the ring has theRconfiguration in the SHV-1 intermediate and has bothRandSconfigurations in the GC1 intermediate. Hydrophobic stacking interactions between the tricyclic C7 substituent and a tyrosine side chain, rather than electrostatic or hydrogen bonding by the C3 carboxylic acid group, dominate in both complexes. The formation of the 1,4- thiazepine ring structures is proposed based on a7-endo-trigcyclization.