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

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.

Automated summary

To develop inhibitors for bacterial deacetylase LpxC, a series of aldotetronic acid-based hydroxamic acids were synthesized and tested for their inhibitory activity. The most potent inhibitor, benzyl ether 17a, was further evaluated for antibacterial activity, bacterial uptake, and susceptibility to efflux pumps. Molecular docking studies were performed to explain the observed structure-activity relationships.