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MARIA VALERIA RAIMONDI

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

  • Authors: 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
  • Publication year: 2022
  • Type: Articolo in rivista
  • OA Link: http://hdl.handle.net/10447/578858

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.