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.
Department of Chemical Biology, Helmholtz Centre for Infection Research (HZI), Inhoffenstr. 7, 38124 Braunschweig, Germany.
Bioorg Chem. 2021 Feb;107:104603. doi: 10.1016/j.bioorg.2020.104603. Epub 2020 Dec 31.
LpxC inhibitors represent a promising class of novel antibiotics selectively combating Gram-negative bacteria. In chiral pool syntheses starting from D- and L-xylose, a series of four 2r,3c,4t-configured C-furanosidic LpxC inhibitors was obtained. The synthesized hydroxamic acids were tested for antibacterial and LpxC inhibitory activity, the acquired biological data were compared with those of previously synthesized C-furanosides, and molecular docking studies were performed to rationalize the observed structure-activity relationships. Additionally, bacterial uptake and susceptibility to efflux pump systems were investigated for the most promising stereoisomers.
LpxC 抑制剂是一类有前途的新型抗生素，可选择性地对抗革兰氏阴性菌。从 D-和 L-木糖起始的手性池合成中，得到了一系列四种 2r、3c、4t-构型的 C-呋喃糖基 LpxC 抑制剂。合成的羟肟酸进行了抗菌和 LpxC 抑制活性测试，获得的生物学数据与之前合成的 C-呋喃糖苷进行了比较，并进行了分子对接研究以合理化观察到的结构-活性关系。此外，还研究了最有前途的立体异构体的细菌摄取和对外排泵系统的敏感性。
