Chiral Pool Synthesis, Biological Evaluation and Molecular Docking Studies of C‐Furanosidic LpxC Inhibitors. (12th March 2019)

• Record Type: Journal Article
• Authors: Dreger, Alexander; Kharwb, Omar; Agoglitta, Oriana; Bülbül, Emre F.; Melesina, Jelena; Sippl, Wolfgang; Holl, Ralph
• Is Part Of: ChemMedChem. Volume 14:Number 8(2019)
• Page Start: 871
• Page End: 886
• Publication Date: 2019-03-12
• Subjects: antibiotics -- C-glycosides -- conformational restriction -- LpxC inhibitors -- molecular docking studies; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201900068
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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 fromd ‐gulono‐γ‐lactone andd ‐ribose, a series of (3 S, 4 R )‐configured dihydroxytetrahydrofuran derivatives was obtained, of which the (2 S, 5 S )‐configured hydroxamic acid15 ((2 S, 3 S, 4 R, 5 S )‐ N, 3, 4‐trihydroxy‐5‐(4‐{[4‐(morpholinomethyl)phenyl]ethynyl}phenyl)tetrahydrofuran‐2‐carboxamide) was found to be the most potent LpxC inhibitor ( K i =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. Abstract : Conformationally constrained inhibitors of the bacterial deacetylase LpxC are a novel class of antibiotics. To gain further insight into the relationship between the stereochemistry of C ‐furanosidic LpxC inhibitors and their antibacterial and LpxC inhibitory activity, chiral pool syntheses of four diastereomeric hydroxamic acids were performed, and the compounds were tested for biological activity. The (2 S, 3 S, 4 R, 5 S )‐configured stereoisomer was found to display the highest inhibitory and antibacterial activity.