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[Display omitted] • Stereoisomeric aldotetronic acid-based LpxC inhibitors were synthesized from 4,6- O -benzylidene- d -glucose and l -arabinitol. • The hydroxamic acids were tested for inhibitory activity toward LpxC and LasB as well as antibacterial properties. • With the help of molecular docking studies, SAR were established. • Bacterial uptake and susceptibility to efflux pump systems were studied. 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 ((2 S ,3 S)-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. [ABSTRACT FROM AUTHOR]

[Display omitted] The bacterial deacetylase LpxC is a promising target for the development of novel antibiotics being selectively active against Gram-negative bacteria. In chiral pool syntheses starting from d - and l -ribose, a series regio- and stereoisomeric monohydroxytetrahydrofuran derivatives was synthesized and tested for LpxC inhibitory and antibacterial activities. Molecular docking studies were performed to rationalize the obtained structure–activity relationships. The (2 S ,3 R ,5 R)-configured 3-hydroxytetrahydrofuran derivative ent- 8 ((2 S ,3 R ,5 R)- N ,3-Dihydroxy-5-(4-{[4-(morpholinomethyl)phenyl]ethynyl}phenyl)tetrahydrofuran-2-carboxamide) was found to be the most potent LpxC inhibitor (K i = 3.5 µM) of the synthesized series of monohydroxytetrahydrofuran derivatives and to exhibit the highest antibacterial activity against E. coli BL21(DE3) and the D22 strain. [ABSTRACT FROM AUTHOR]

• 3,4- trans -configured C -furanosides were synthesized from D- and L-xylose. • The hydroxamic acids were tested for LpxC inhibitory and antibacterial activity. • With the help of molecular docking studies, SAR were established. • Bacterial uptake and susceptibility to efflux pump systems were studied. LpxC inhibitors represent a promising class of novel antibiotics selectively combating Gram-negative bacteria. In chiral pool syntheses starting from D- and L-xylose, a series of four 2 r ,3 c ,4 t -configured C -furanosidic LpxC inhibitors was obtained. The synthesized hydroxamic acids were tested for antibacterial and LpxC inhibitory activity, the acquired biological data were compared with those of previously synthesized C -furanosides, and molecular docking studies were performed to rationalize the observed structure-activity relationships. Additionally, bacterial uptake and susceptibility to efflux pump systems were investigated for the most promising stereoisomers. [ABSTRACT FROM AUTHOR]