: In order to develop novel inhibitors of the bacterial deacetylase LpxC bearing a substituent to target the UDP binding site of the enzyme, a series of aldotetronic acid-based hydroxamic acids was accessed in chiral pool syntheses starting from 4,6-O-benzylidene-d-glucose and l-arabinitol. The synthesized hydroxamic acids were tested for LpxC inhibitory activity in vitro, revealing benzyl ether 17a ((2S,3S)-4-(benzyloxy)-N,3-dihydroxy-2-[(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)oxy]butanamide) as the most potent LpxC inhibitor. This compound was additionally tested for antibacterial activity against a panel of clinically relevant Gram-negative bacteria, bacterial uptake, and susceptibility to efflux pumps. Molecular docking studies were performed to rationalize the observed structure-activity relationships.

Wimmer, S., Hoff, K., Martin, B., Grewer, M., Denni, L., Lascorz Massanet, R., et al. (2022). Synthesis, biological evaluation, and molecular docking studies of aldotetronic acid-based LpxC inhibitors. BIOORGANIC CHEMISTRY, 131, 1-21 [10.1016/j.bioorg.2022.106331].

Synthesis, biological evaluation, and molecular docking studies of aldotetronic acid-based LpxC inhibitors

Raimondi, Maria Valeria
Investigation
;
2022-12-19

Abstract

: In order to develop novel inhibitors of the bacterial deacetylase LpxC bearing a substituent to target the UDP binding site of the enzyme, a series of aldotetronic acid-based hydroxamic acids was accessed in chiral pool syntheses starting from 4,6-O-benzylidene-d-glucose and l-arabinitol. The synthesized hydroxamic acids were tested for LpxC inhibitory activity in vitro, revealing benzyl ether 17a ((2S,3S)-4-(benzyloxy)-N,3-dihydroxy-2-[(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)oxy]butanamide) as the most potent LpxC inhibitor. This compound was additionally tested for antibacterial activity against a panel of clinically relevant Gram-negative bacteria, bacterial uptake, and susceptibility to efflux pumps. Molecular docking studies were performed to rationalize the observed structure-activity relationships.
Settore CHIM/08 - Chimica Farmaceutica
https://www.sciencedirect.com/science/article/abs/pii/S0045206822007386?via=ihub
Wimmer, S., Hoff, K., Martin, B., Grewer, M., Denni, L., Lascorz Massanet, R., et al. (2022). Synthesis, biological evaluation, and molecular docking studies of aldotetronic acid-based LpxC inhibitors. BIOORGANIC CHEMISTRY, 131, 1-21 [10.1016/j.bioorg.2022.106331].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/578858
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