Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Zografou, 15701 Athens, Greece.
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
J Med Chem. 2021 Jan 14;64(1):404-416. doi: 10.1021/acs.jmedchem.0c01143. Epub 2020 Dec 28.
In this study, a new class of bifunctional inhibitors of bacterial ureases, important molecular targets for antimicrobial therapies, was developed. The structures of the inhibitors consist of a combination of a phosphonate or (2-carboxyethyl)phosphinate functionality with a catechol-based fragment, which are designed for complexation of the catalytic nickel ions and covalent bonding with the thiol group of Cys322, respectively. Compounds with three types of frameworks, including β-3,4-dihydroxyphenyl-, α-3,4-dihydroxybenzyl-, and α-3,4-dihydroxybenzylidene-substituted derivatives, exhibited complex and varying structure-dependent kinetics of inhibition. Among irreversible binders, methyl β-(3,4-dihydroxyphenyl)-β-(2-carboxyethyl)phosphorylpropionate was observed to be a remarkably reactive inhibitor of urease (/ = 10 420 s M). The high potential of this group of compounds was also confirmed in whole-cell-based inhibition assays. Some compounds followed slow-binding and reversible kinetics, e.g., methyl β-(3,4-dihydroxyphenyl)-β-phosphonopropionate, with * = 0.13 μM, and an atypical low dissociation rate (residence time τ = 205 min).
在这项研究中，开发了一类新的细菌脲酶双功能抑制剂，这是抗菌治疗的重要分子靶标。抑制剂的结构由膦酸酯或（2-羧乙基）膦酸酯功能与儿茶酚基片段的组合组成，分别设计用于与催化镍离子络合和与 Cys322 的硫醇基团共价键合。具有三种类型结构的化合物，包括β-3,4-二羟基苯基、α-3,4-二羟基苄基和α-3,4-二羟基苯亚甲基取代衍生物，表现出复杂的、结构依赖性的抑制动力学。在不可逆结合物中，观察到甲基 β-(3,4-二羟基苯基)-β-(2-羧乙基)膦酰基丙酸酯是一种非常活跃的脲酶抑制剂（/ = 10420 s M）。该类化合物的高潜力也在基于全细胞的抑制测定中得到了证实。一些化合物遵循慢结合和可逆动力学，例如甲基 β-(3,4-二羟基苯基)-β-膦酸丙酯，* = 0.13 μM，以及异常低的解离速率（停留时间 τ = 205 分钟）。
