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

Amidohydrolases / antagonists & inhibitors Anti-Bacterial Agents / chemistry Bacteria / metabolism Binding Sites Enzyme Inhibitors / chemistry Escherichia coli Hydroxamic Acids / pharmacology Molecular Docking Simulation Structure-Activity Relationship
Aldotetronic acid derivatives Antibiotics Bacterial uptake LasB LpxC inhibitors Molecular-docking studies

Journal

Bioorganic chemistry
ISSN: 1090-2120
Titre abrégé: Bioorg Chem
Pays: United States
ID NLM: 1303703

Informations de publication

Date de publication:
02 2023
Historique:
received: 14 09 2022
revised: 13 12 2022
accepted: 15 12 2022
pubmed: 2 1 2023
medline: 21 1 2023
entrez: 1 1 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.bioorg.2022.106331 PMID: 36587505
pubmed: 36587505
pii: S0045-2068(22)00738-6
doi: 10.1016/j.bioorg.2022.106331
pii:
doi:

Substances chimiques

Amidohydrolases EC 3.5.-
Anti-Bacterial Agents 0
Enzyme Inhibitors 0
Hydroxamic Acids 0
UDP-3-O-acyl-N-acetylglucosamine deacetylase EC 3.5.1.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

106331

Informations de copyright

Copyright © 2022 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Auteurs

Stefan Wimmer (S)

Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.

Katharina Hoff (K)

Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Germany.

Benedikt Martin (B)

Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, 48149 Münster, Germany.

Martin Grewer (M)

Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, 48149 Münster, Germany.

Laura Denni (L)

Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.

Raquel Lascorz Massanet (R)

Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.

Maria Valeria Raimondi (MV)

Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy.

Emre F Bülbül (EF)

Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120 Halle (Saale), Germany.

Jelena Melesina (J)

Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120 Halle (Saale), Germany.

Sven-Kevin Hotop (SK)

Department of Chemical Biology, Helmholtz Centre for Infection Research (HZI), Inhoffenstr. 7, 38124 Braunschweig, Germany.

Jörg Haupenthal (J)

Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Campus E8.1, 66123 Saarbrücken, Germany.

Holger Rohde (H)

German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Germany; Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Peter Heisig (P)

Institute of Biochemistry and Molecular Biology, University of Hamburg, Bundesstr. 45, 20146 Hamburg, Germany.

Anna K H Hirsch (AKH)

Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Campus E8.1, 66123 Saarbrücken, Germany; Helmholtz International Lab for Anti-infectives, Germany; Department of Pharmacy, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany.

Mark Brönstrup (M)

Department of Chemical Biology, Helmholtz Centre for Infection Research (HZI), Inhoffenstr. 7, 38124 Braunschweig, Germany; Helmholtz International Lab for Anti-infectives, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany.

Wolfgang Sippl (W)

Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120 Halle (Saale), Germany.

Ralph Holl (R)

Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Germany. Electronic address: ralph.holl@uni-hamburg.de.

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Classifications MeSH

questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Amidohydrolases › Synthesis, biological evaluation, and...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antibactériens › Synthesis, biological evaluation, and...
questionsmedicales.fr › Bactéries › Synthesis, biological evaluation, and...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › Synthesis, biological evaluation, and...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Synthesis, biological evaluation, and...
questionsmedicales.fr › Bactéries › Proteobacteria › Gammaproteobacteria › Enterobacteriaceae › Escherichia › Escherichia coli › Synthesis, biological evaluation, and...
questionsmedicales.fr › Composés chimiques organiques › Acides carboxyliques › Hydroxyacides › Acides hydroxamiques › Synthesis, biological evaluation, and...
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de docking moléculaire › Synthesis, biological evaluation, and...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Synthesis, biological evaluation, and...