Published in:
ChemMedChem, 14 (2019) 8, Seite 871-886
Language:
English
DOI:
10.1002/cmdc.201900068
ISSN:
1860-7179;
1860-7187
Origination:
Footnote:
Description:
AbstractInhibitors 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 (Ki=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.