Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity
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Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity. / Mielniczuk, Sebastian; Hoff, Katharina; Baselious, Fady; Li, Yunqi; Haupenthal, Jörg; Kany, Andreas M; Riedner, Maria; Rohde, Holger; Rox, Katharina; Hirsch, Anna K H; Krimm, Isabelle; Sippl, Wolfgang; Holl, Ralph.
In: J MED CHEM, Vol. 67, No. 19, 10.10.2024, p. 17363-17391.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity
AU - Mielniczuk, Sebastian
AU - Hoff, Katharina
AU - Baselious, Fady
AU - Li, Yunqi
AU - Haupenthal, Jörg
AU - Kany, Andreas M
AU - Riedner, Maria
AU - Rohde, Holger
AU - Rox, Katharina
AU - Hirsch, Anna K H
AU - Krimm, Isabelle
AU - Sippl, Wolfgang
AU - Holl, Ralph
PY - 2024/10/10
Y1 - 2024/10/10
N2 - 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.
AB - 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.
KW - Amidohydrolases/antagonists & inhibitors
KW - Structure-Activity Relationship
KW - Anti-Bacterial Agents/pharmacology
KW - Molecular Docking Simulation
KW - Enzyme Inhibitors/pharmacology
KW - Microbial Sensitivity Tests
KW - Molecular Dynamics Simulation
KW - Hydroxamic Acids/chemistry
KW - Humans
KW - Animals
U2 - 10.1021/acs.jmedchem.4c01262
DO - 10.1021/acs.jmedchem.4c01262
M3 - SCORING: Journal article
C2 - 39303295
VL - 67
SP - 17363
EP - 17391
JO - J MED CHEM
JF - J MED CHEM
SN - 0022-2623
IS - 19
ER -