Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 24, Issue 5, Pages 1032-1044Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.01.029
Keywords
LpxC inhibitors; Structure-activity relationships; Glyceric acid derivatives; Chiral pool synthesis; Enantioselective desymmetrization; Molecular docking studies
Funding
- Deutsche Forschungsgemeinschaft [HO 5220/2-1]
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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 derivatives 7 show antibacterial activities against two Escherichia coli strains exceeding the ones of their respective regioisomes 6. (C) 2016 Elsevier Ltd. All rights reserved.
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