Benzimidazole and Benzoxazole Zinc Chelators as Inhibitors of Metallo‐β‐Lactamase NDM‐1,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.)

Benzimidazole and Benzoxazole Zinc Chelators as Inhibitors of Metallo‐β‐Lactamase NDM‐1
ChemMedChem ( IF 3.6 ) Pub Date : 2020-11-19 , DOI: 10.1002/cmdc.202000607
Abigail C Jackson ₁ , Tyler B J Pinter ₁ , Daniel C Talley ₂ , Adnan Baker-Agha ₂ , Dhruvil Patel ₂ , Paul J Smith ₂ , Katherine J Franz ₁

Affiliation

Bacterial expression of β‐lactamases, which hydrolyze β‐lactam antibiotics, contributes to the growing threat of antibacterial drug resistance. Metallo‐β‐lactamases, such as NDM‐1, use catalytic zinc ions in their active sites and hydrolyze nearly all clinically available β‐lactam antibiotics. Inhibitors of metallo‐β‐lactamases are urgently needed to overcome this resistance mechanism. Zinc‐binding compounds are promising leads for inhibitor development, as many NDM‐1 inhibitors contain zinc‐binding pharmacophores. Here, we evaluated 13 chelating agents containing benzimidazole and benzoxazole scaffolds as NDM‐1 inhibitors. Six of the compounds showed potent inhibitory activity with IC₅₀ values as low as 0.38 μM, and several compounds restored the meropenem susceptibility of NDM‐1‐expressing E. coli. Spectroscopic and docking studies suggest ternary complex formation as the mechanism of inhibition, making these compounds promising for development as NDM‐1 inhibitors.

中文翻译：

苯并咪唑和苯并恶唑锌螯合剂作为金属-β-内酰胺酶 NDM-1 的抑制剂

细菌表达β-内酰胺酶，可水解β-内酰胺抗生素，导致抗菌药物耐药性的威胁日益严重。金属-β-内酰胺酶，例如 NDM-1，在其活性位点使用催化锌离子，并水解几乎所有临床上可用的 β-内酰胺抗生素。迫切需要金属-β-内酰胺酶抑制剂来克服这种耐药机制。锌结合化合物是抑制剂开发的有前景的先导化合物，因为许多 NDM-1 抑制剂含有锌结合药效团。在这里，我们评估了 13 种含有苯并咪唑和苯并恶唑支架的螯合剂作为 NDM-1 抑制剂。其中六种化合物显示出有效的抑制活性，IC ₅₀值低至 0.38 μM，并且几种化合物恢复了表达 NDM-1 的大肠杆菌对美罗培南的敏感性。光谱和对接研究表明三元复合物的形成是抑制机制，使得这些化合物有望作为 NDM-1 抑制剂进行开发。

更新日期：2020-11-19

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