Rh 催化的乙烷-1,2-二硫醇和丙烷-1,3-二硫醇的去对称化反应生成金属β-内酰胺酶抑制剂。

Institute of Chemistry, Saint Petersburg State University 26 Universitetskii prospect, Peterhof, 198905, Russia.

Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Straße 40, 60596, Frankfurt, Germany.

ChemMedChem. 2021 Nov 19;16(22):3410-3417. doi: 10.1002/cmdc.202100344. Epub 2021 Aug 3.

Diversity-oriented synthesis (DOS) is a rich source for novel lead structures in Medicinal Chemistry. In this study, we present a DOS-compatible method for synthesis of compounds bearing a free thiol moiety. The procedure relies on Rh(II)-catalyzed coupling of dithiols to diazo building blocks. The synthetized library was probed against metallo-β-lactamases (MBLs) NDM-1 and VIM-1. Biochemical and biological evaluation led to identification of novel potent MBL inhibitors with antibiotic adjuvant activity.

导向多样性合成（DOS）是药物化学中新型先导结构的丰富来源。在这项研究中，我们提出了一种与 DOS 兼容的方法，用于合成含有游离巯基部分的化合物。该方法依赖于 Rh(II)催化的二硫醇与重氮砌块的偶联。所合成的文库针对金属β-内酰胺酶（MBLs）NDM-1 和 VIM-1 进行了探测。生物化学和生物学评估导致了具有抗生素佐剂活性的新型强效 MBL 抑制剂的鉴定。