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Chiral Pool Synthesis, Biological Evaluation and Molecular Docking Studies of C ‐Furanosidic LpxC Inhibitors
Author(s) -
Dreger Alexander,
Kharwb Omar,
Agoglitta Oriana,
Bülbül Emre F.,
Melesina Jelena,
Sippl Wolfgang,
Holl Ralph
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900068
Subject(s) - chemistry , stereochemistry , hydroxamic acid , tetrahydrofuran , docking (animal) , lactone , antibacterial activity , biological activity , bacteria , biochemistry , in vitro , biology , medicine , nursing , solvent , genetics
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 from d ‐gulono‐γ‐lactone and d ‐ribose, a series of (3 S ,4 R )‐configured dihydroxytetrahydrofuran derivatives was obtained, of which the (2 S ,5 S )‐configured hydroxamic acid 15 ((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 μ m ), 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.