新型β-内酰胺作为碳青霉烯过渡态类似物：金属β-内酰胺酶广谱抑制剂的合成。
New β-phospholactam as a carbapenem transition state analog: Synthesis of a broad-spectrum inhibitor of metallo-β-lactamases.
机构信息
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710069, PR China.
出版信息
Bioorg Med Chem Lett. 2013 Nov 1;23(21):5855-9. doi: 10.1016/j.bmcl.2013.08.098. Epub 2013 Sep 8.
Abstract
In an effort to test whether a transition state analog is an inhibitor of the metallo-β-lactamases, a phospholactam analog of carbapenem has been synthesized and characterized. The phospholactam 1 proved to be a weak, time-dependent inhibitor of IMP-1 (70%), CcrA (70%), L1 (70%), NDM-1 (53%), and Bla2 (94%) at an inhibitor concentration of 100μM. The phospholactam 1 activated ImiS and BcII at the same concentration. Docking studies were used to explain binding and to offer suggestions for modifications to the phospholactam scaffold to improve binding affinities.
摘要
为了测试过渡态类似物是否为金属β-内酰胺酶的抑制剂，已合成并表征了碳青霉烯的膦酰内酰胺类似物。在抑制剂浓度为 100μM 时，膦酰内酰胺 1 被证明对 IMP-1（70%）、CcrA（70%）、L1（70%）、NDM-1（53%）和 Bla2（94%）是一种弱的、时间依赖性抑制剂。在相同浓度下，膦酰内酰胺 1 激活了 ImiS 和 BcII。对接研究用于解释结合，并为改善结合亲和力对膦酰内酰胺支架提出了修改建议。
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