Synthesis and biological evaluation of C-ethynyl furanosides as LpxC inhibitors. Issue 6 (11th February 2015)

• Record Type: Journal Article
• Authors: Jana, Sunit Kumar; Löppenberg, Marius; Daniliuc, Constantin G.; Holl, Ralph
• Is Part Of: Tetrahedron. Volume 71:Issue 6(2015)
• Page Start: 956
• Page End: 966
• Publication Date: 2015-02-11
• Subjects: C-Ethynyl glycosides -- Stereocontrolled synthesis -- C–C coupling reactions -- LpxC inhibitors -- Structure–activity relationships; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2014.12.069
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: Lipopolysaccharides (LPS) are the main component of the outer leaflet of the outer membrane of Gram-negative bacteria, serving as a permeability barrier, which protects the bacteria from many antibiotics. LpxC, a Zn 2+ -dependent enzyme, catalyzes the first irreversible step of the biosynthesis of lipid A, the hydrophobic membrane anchor of LPS being essential for cell viability. As LpxC inhibitors represent a promising class of novel antibiotics, a series of C -ethynyl furanosides was stereoselectively synthesized and tested for inhibitory activity against LpxC. In the key steps of the synthesis, terminal alkynes10 and13 were subjected to Sonogashira couplings and Eglinton reactions. Using these C–C coupling reactions, long and rigid lipophilic side chains could be introduced to the C -glycosidic LpxC inhibitors. The biological evaluation of the synthesized compounds revealed that the α-configured C -phenylethynyl glycoside5a possesses inhibitory activity against LpxC with a K i value of 14.7 μm. Graphical abstract: