Department of Chemistry, 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.
ChemMedChem. 2019 Apr 17;14(8):871-886. doi: 10.1002/cmdc.201900068. Epub 2019 Mar 12.
Inhibitors of the bacterial deacetylase LpxC are a promising class of novel antibiotics, being selectively active against Gram-negative bacteria. To improve the biological activity of reported C-furanosidic LpxC inhibitors, the stereochemistry at positions 3 and 4 of the tetrahydrofuran ring was varied. In chiral pool syntheses starting from d-gulono-γ-lactone and d-ribose, a series of (3S,4R)-configured dihydroxytetrahydrofuran derivatives was obtained, of which the (2S,5S)-configured hydroxamic acid 15 ((2S,3S,4R,5S)-N,3,4-trihydroxy-5-(4-{[4-(morpholinomethyl)phenyl]ethynyl}phenyl)tetrahydrofuran-2-carboxamide) was found to be the most potent LpxC inhibitor (K =0.4 μm), exhibiting the highest antibacterial activity against E. coli BL21 (DE3) and the D22 strain. Additionally, molecular docking studies were performed to rationalize the obtained structure-activity relationships.
细菌去乙酰化酶 LpxC 的抑制剂是一类很有前途的新型抗生素，对革兰氏阴性菌具有选择性活性。为了提高已报道的 C-呋喃糖基 LpxC 抑制剂的生物活性，我们改变了四氢呋喃环 3 位和 4 位的立体化学。从 d-古洛糖-γ-内酯和 d-核糖开始的手性池合成中，得到了一系列（3S,4R）构型的二羟四氢呋喃衍生物，其中（2S,5S）构型的羟肟酸 15（(2S,3S,4R,5S)-N,3,4-三羟基-5-(4-[[4-(吗啉代甲基)苯基]乙炔基]苯基)四氢呋喃-2-甲酰胺）是最有效的 LpxC 抑制剂（K =0.4 μm），对大肠杆菌 BL21（DE3）和 D22 菌株表现出最高的抗菌活性。此外，还进行了分子对接研究，以合理推断获得的构效关系。
