Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
Org Biomol Chem. 2013 Sep 28;11(36):6056-70. doi: 10.1039/c3ob41082j.
Inhibitors of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represent promising candidates for the development of antibiotics possessing a so far unexploited mechanism of action. In a chiral pool synthesis, starting from the D-mannose derived mannonolactone 4, conformationally constrained C-glycosidic as well as open chained hydroxamic acids with a defined stereochemistry were prepared. Diversity was introduced by performing C–C coupling reactions like the Sonogashira and Suzuki cross-coupling reactions. The biological evaluation of the synthesized compounds revealed that in the case of the C-glycosides a long, linear and rigid hydrophobic side chain is required for antibiotic activity against E. coli. The open chain derivatives show higher biological activity than the conformationally constrained C-glycosides. The morpholinomethyl substituted open chain derivative 43, being the most potent compound presented in this paper, inhibits LpxC with a Ki value of 0.35 μM and represents a promising lead structure.
UDP-3-O-[(R)-3-羟基十四烷酰基]-N-乙酰葡萄糖胺脱乙酰酶（LpxC）抑制剂是开发具有迄今未开发作用机制的抗生素的有希望的候选物。在手性池合成中，从 D-甘露糖衍生的甘露内酯 4 开始，制备了具有确定立体化学的构象受限的 C-糖基和开链羟肟酸。通过进行 Sonogashira 和 Suzuki 交叉偶联反应等 C-C 偶联反应引入了多样性。所合成化合物的生物学评价表明，在 C-糖苷的情况下，长的、线性的和刚性的疏水性侧链对于针对大肠杆菌的抗生素活性是必需的。开链衍生物显示出比构象受限的 C-糖苷更高的生物活性。在本文中呈现的最有效化合物是取代吗啉甲基的开链衍生物 43，它抑制 LpxC 的 Ki 值为 0.35 μM，是一种很有前途的先导结构。
