Synthesis and biological evaluation of enantiomerically pure glyceric acid derivatives as LpxC inhibitors. Issue 5 (1st March 2016)

• Record Type: Journal Article
• Authors: Tangherlini, Giovanni; Torregrossa, Tullio; Agoglitta, Oriana; Köhler, Jens; Melesina, Jelena; Sippl, Wolfgang; Holl, Ralph
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 5(2016)
• Page Start: 1032
• Page End: 1044
• Publication Date: 2016-03-01
• Subjects: LpxC inhibitors -- Structure–activity relationships -- Glyceric acid derivatives -- Chiral pool synthesis -- Enantioselective desymmetrization -- Molecular docking studies; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.01.029
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Inhibitors of the UDP-3-O-[( R )-3-hydroxymyristoyl]- N -acetylglucosamine deacetylase (LpxC) represent a promising class of novel antibiotics, selectively combating Gram-negative bacteria. In order to elucidate the impact of the hydroxymethyl groups of diol ( S, S )-4 on the inhibitory activity against LpxC, glyceric acid ethers ( R )-7a, ( S )-7a, ( R )-7b, and ( S )-7b, lacking the hydroxymethyl group in benzylic position, were synthesized. The compounds were obtained in enantiomerically pure form by a chiral pool synthesis and a lipase-catalyzed enantioselective desymmetrization, respectively. The enantiomeric hydroxamic acids ( R )-7b ( K i = 230 nM) and ( S )-7b ( K i = 390 nM) show promising enzyme inhibition. However, their inhibitory activities do not substantially differ from each other leading to a low eudismic ratio. Generally, the synthesized glyceric acid derivatives7 show antibacterial activities against two Escherichia coli strains exceeding the ones of their respective regioisomes6 .