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RESEARCH PRODUCT
Synthesis, biological evaluation, and molecular docking studies of aldotetronic acid-based LpxC inhibitors
Wimmer StefanHoff KatharinaMartin BenediktGrewer MartinDenni LauraLascorz Massanet RaquelRaimondi Maria ValeriaBülbül Emre FMelesina JelenaHotop Sven-kevinHaupenthal JörgRohde HolgerHeisig PeterHirsch Anna K HBrönstrup MarkSippl WolfgangHoll Ralphsubject
AntibioticsBacterial uptakeLpxC inhibitorsOrganic ChemistryDrug DiscoveryAldotetronic acid derivativesMolecular-docking studiesLasBMolecular BiologyBiochemistrySettore CHIM/08 - Chimica Farmaceuticadescription
: 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2022-09-14 |