Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity

In a fragment-based approach using NMR spectroscopy,
benzyloxyacetohydroxamic
acid-derived inhibitors of the bacterial deacetylase LpxC bearing
a substituent to target the uridine diphosphate-binding site of the
enzyme were developed. By appending privileged fragments via a suitable
linker, potent LpxC inhibitors with promising antibacterial activities
could be obtained, like the one-digit nanomolar LpxC inhibitor (S)-13j [Ki (EcLpxC C63A) = 9.5 nM; Ki (PaLpxC): 5.6 nM].
To rationalize the observed structure–activity relationships,
molecular docking and molecular dynamics studies were performed. Initial
in vitro absorption–distribution–metabolism–excretion–toxicity
(ADMET) studies of the most potent compounds have paved the way for
multiparameter optimization of our newly developed isoserine-based
amides.