α-Triazolylboronic Acids: A Promising Scaffold for Effective Inhibitors of KPCs.,ChemMedChem

当前位置： X-MOL 学术 › ChemMedChem › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

α-Triazolylboronic Acids: A Promising Scaffold for Effective Inhibitors of KPCs.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-05-27 , DOI: 10.1002/cmdc.202000126
Maria Luisa Introvigne _{1,

2} , Magdalena A Taracila _{3,

4} , Fabio Prati ₂ , Emilia Caselli ₂ , Robert A Bonomo _{3,

4,

5,

6}

Affiliation

Boronic acids are known reversible covalent inhibitors of serine β‐lactamases. The selectivity and high potency of specific boronates bearing an amide side chain that mimics the β‐lactam's amide side chain have been advanced in several studies. Herein, we describe a new class of boronic acids in which the amide group is replaced by a bioisostere triazole. The boronic acids were obtained in a two‐step synthesis that relies on the solid and versatile copper‐catalyzed azide–alkyne cycloaddition (CuAAC) followed by boronate deprotection. All of the compounds show very good inhibition of the Klebsiella pneumoniae carbapenemase KPC‐2, with K _i values ranging from 1 nM to 1 μM, and most of them are able to restore cefepime activity against K. pneumoniae harboring bla _KPC‐2. In particular, compound 1 e , bearing a sulfonamide substituted by a thiophene ring, proved to be an excellent KPC‐2 inhibitor (K _i=30 nM); it restored cefepime susceptibility in KPC‐Kpn cells (MIC=0.5 μg/mL) with values similar to that of vaborbactam (K _i=20 nM, MIC in KPC‐Kpn 0.5 μg/mL). Our findings suggest that α‐triazolylboronates might represent an effective scaffold for the treatment of KPC‐mediated infections.

中文翻译：

α-三唑基硼酸：一种有前途的 KPC 有效抑制剂支架。

硼酸是已知的丝氨酸β-内酰胺酶的可逆共价抑制剂。带有模拟β-内酰胺酰胺侧链的特定硼酸酯的选择性和高效力在多项研究中得到了进步。在此，我们描述了一类新的硼酸，其中酰胺基团被生物电子等排体三唑取代。硼酸是通过两步合成获得的，该合成依赖于固体且通用的铜催化叠氮化物-炔环加成（CuAAC），然后进行硼酸酯脱保护。所有化合物均对肺炎克雷伯菌碳青霉烯酶 KPC-2 表现出非常好的抑制作用，K _i值范围为 1 nM 至 1 μM，并且大多数化合物能够恢复头孢吡肟对携带bla _{KPC-2 的}肺炎克雷伯菌的活性。特别是，带有被噻吩环取代的磺酰胺的化合物1 e被证明是一种优异的 KPC-2 抑制剂（K _i = 30 nM）；它恢复了 KPC-Kpn 细胞中头孢吡肟的敏感性 (MIC=0.5 μg/mL)，其值与伐波巴坦相似 ( K _i =20 nM，KPC-Kpn 中的 MIC 0.5 μg/mL)。我们的研究结果表明，α-三唑基硼酸盐可能是治疗 KPC 介导的感染的有效支架。

更新日期：2020-07-20

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11