Development\nof Fragment-Based Inhibitors of the Bacterial\nDeacetylase LpxC with Low Nanomolar Activity

In a fragment-based approach using NMR spectroscopy,\nbenzyloxyacetohydroxamic\nacid-derived inhibitors of the bacterial deacetylase LpxC bearing\na substituent to target the uridine diphosphate-binding site of the\nenzyme were developed. By appending privileged fragments via a suitable\nlinker, potent LpxC inhibitors with promising antibacterial activities\ncould be obtained, like the one-digit nanomolar LpxC inhibitor (<i>S</i>)-<b>13j</b> [<i>K</i><sub><i>i</i></sub> (<i>Ec</i>LpxC C63A) = 9.5 nM; <i>K</i><sub><i>i</i></sub> (<i>Pa</i>LpxC): 5.6 nM].\nTo rationalize the observed structure–activity relationships,\nmolecular docking and molecular dynamics studies were performed. Initial\nin vitro absorption–distribution–metabolism–excretion–toxicity\n(ADMET) studies of the most potent compounds have paved the way for\nmultiparameter optimization of our newly developed isoserine-based\namides.