Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Germany; Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, 48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster, Germany.
Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Germany; NRW Graduate School of Chemistry, University of Münster, Germany.
Bioorg Med Chem. 2019 May 15;27(10):1997-2018. doi: 10.1016/j.bmc.2019.03.056. Epub 2019 Mar 30.
The Zn-dependent deacetylase LpxC is an essential enzyme in Gram-negative bacteria, which has been validated as antibacterial drug target. Herein we report the chiral-pool synthesis of novel d- and l-proline-derived 3,4-dihydroxypyrrolidine hydroxamates and compare their antibacterial and LpxC inhibitory activities with the ones of 4-monosubstituted and 3,4-unsubstituted proline derivatives. With potent antibacterial activities against several Gram-negative pathogens, the l-proline-based tertiary amine 41g ((S)-N-hydroxy-1-(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)pyrrolidine-2-carboxamide) was found to be the most active antibacterial compound within the investigated series, also showing some selectivity toward EcLpxC (K = 1.4 μM) over several human MMPs.
锌依赖的去乙酰化酶 LpxC 是革兰氏阴性菌中的一种必需酶，已被验证为抗菌药物靶点。本文报道了新型 d-和 l-脯氨酸衍生的 3,4-二羟基吡咯烷羟胺的手性池合成，并比较了它们与 4-单取代和 3,4-未取代脯氨酸衍生物的抗菌和 LpxC 抑制活性。具有针对几种革兰氏阴性病原体的强大抗菌活性，基于 l-脯氨酸的叔胺 41g((S)-N-羟基-1-(4-({[4-(吗啉甲基)苯基]乙炔基}苯乙基)吡咯烷-2-甲酰胺)是在所研究的系列中最具活性的抗菌化合物，对 EcLpxC(K=1.4μM)也表现出一定的选择性，优于几种人 MMP。
