| Přispěvatelé: |
Wimmer, Stefan, Hoff, Katharina, Martin, Benedikt, Grewer, Martin, Denni, Laura, Lascorz Massanet, Raquel, Raimondi, Maria Valeria, Bülbül, Emre F, Melesina, Jelena, Hotop, Sven-Kevin, Haupenthal, Jörg, Rohde, Holger, Heisig, Peter, Hirsch, Anna K H, Brönstrup, Mark, Sippl, Wolfgang, Holl, Ralph |
| Popis: |
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. |
