Development of small-molecule inhibitors of fatty acyl-AMP and fatty acyl-CoA ligases in Mycobacterium tuberculosis.

Adenosine / analogs & derivatives Animals Antitubercular Agents / chemical synthesis Bacterial Proteins / antagonists & inhibitors Chlorocebus aethiops Coenzyme A Ligases / antagonists & inhibitors Enzyme Inhibitors / chemical synthesis Microbial Sensitivity Tests Molecular Structure Mycobacterium tuberculosis / drug effects Structure-Activity Relationship Sulfonamides / chemical synthesis Vero Cells
Acyl-AMS analogs FAAL28 FACL19 Fatty acyl-AMP ligases Fatty acyl-CoA ligases Mycobacterium tuberculosis

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
01 Sep 2020
Historique:
received: 08 02 2020
revised: 07 04 2020
accepted: 27 04 2020
pubmed: 24 6 2020
medline: 7 4 2021
entrez: 24 6 2020
Statut: ppublish

Résumé

Lipid metabolism in Mycobacterium tuberculosis (Mtb) relies on 34 fatty acid adenylating enzymes (FadDs) that can be grouped into two classes: fatty acyl-CoA ligases (FACLs) involved in lipid and cholesterol catabolism and long chain fatty acyl-AMP ligases (FAALs) involved in biosynthesis of the numerous essential and virulence-conferring lipids found in Mtb. The precise biochemical roles of many FACLs remain poorly characterized while the functionally non-redundant FAALs are much better understood. Here we describe the systematic investigation of 5'-O-[N-(alkanoyl)sulfamoyl]adenosine (alkanoyl adenosine monosulfamate, alkanoyl-AMS) analogs as potential multitarget FadD inhibitors for their antitubercular activity and biochemical selectivity towards representative FAAL and FACL enzymes. We identified several potent compounds including 12-azidododecanoyl-AMS 28, 11-phenoxyundecanoyl-AMS 32, and nonyloxyacetyl-AMS 36 with minimum inhibitory concentrations (MICs) against M. tuberculosis ranging from 0.098 to 3.13 μM. Compound 32 was notable for its impressive biochemical selectivity against FAAL28 (apparent K

Identifiants

DOI: 10.1016/j.ejmech.2020.112408 PMID: 32574901 PMC: PMC7415619
pubmed: 32574901
pii: S0223-5234(20)30379-2
doi: 10.1016/j.ejmech.2020.112408
pmc: PMC7415619
mid: NIHMS1606281
pii:
doi:

Substances chimiques

Antitubercular Agents 0
Bacterial Proteins 0
Enzyme Inhibitors 0
Sulfonamides 0
Coenzyme A Ligases EC 6.2.1.-
Adenosine K72T3FS567

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

112408

Subventions

Organisme : NIAID NIH HHS
ID : R01 AI136445
Pays : United States
Organisme : NIAID NIH HHS
ID : U54 AI057153
Pays : United States

Informations de copyright

Copyright © 2020 Elsevier Masson SAS. 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.

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Auteurs

Marzena Baran (M)

Department of Medicinal Chemistry, University of Minnesota, 8-101 WDH, 308 Harvard Street SE, Minneapolis, MN, 55455, United States.

Kimberly D Grimes (KD)

Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN, 55455, United States.

Paul A Sibbald (PA)

Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN, 55455, United States.

Peng Fu (P)

Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN, 55455, United States.

Helena I M Boshoff (HIM)

Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD, 20892, United States.

Daniel J Wilson (DJ)

Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN, 55455, United States.

Courtney C Aldrich (CC)

Department of Medicinal Chemistry, University of Minnesota, 8-101 WDH, 308 Harvard Street SE, Minneapolis, MN, 55455, United States; Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN, 55455, United States. Electronic address: aldri015@umn.edu.

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Classifications MeSH

questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléosides › Ribonucléosides › Adénosine › Development of small-molecule inhibitors of...
questionsmedicales.fr › Eucaryotes › Animaux › Development of small-molecule inhibitors of...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antibactériens › Antituberculeux › Development of small-molecule inhibitors of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines bactériennes › Development of small-molecule inhibitors of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Cercopithecidae › Cercopithecinae › Cercopithecus › Cercopithecus aethiops › Development of small-molecule inhibitors of...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Ligases › Carbon-sulfur ligases › Coenzyme A ligases › Development of small-molecule inhibitors of...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Development of small-molecule inhibitors of...
questionsmedicales.fr › Techniques d'investigation › Évaluation préclinique de médicament › Tests de sensibilité microbienne › Development of small-molecule inhibitors of...
questionsmedicales.fr › Phénomènes chimiques › Structure moléculaire › Development of small-molecule inhibitors of...
questionsmedicales.fr › Bactéries › Bactéries à Gram positif › Bâtonnets à Gram positif › Bâtonnets asporogènes à Gram positif › Bâtonnets asporogènes réguliers à Gram positif › Mycobacteriaceae › Mycobacterium › Mycobacterium tuberculosis › Development of small-molecule inhibitors of...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Development of small-molecule inhibitors of...
questionsmedicales.fr › Composés chimiques organiques › Composés du soufre › Sulfones › Sulfonamides › Development of small-molecule inhibitors of...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules Vero › Development of small-molecule inhibitors of...