Synthesis and structure-activity relationship studies of original cyclic diadenosine derivatives as nanomolar inhibitors of NAD kinase from pathogenic bacteria

Nicotinamide adenine dinucleotide kinases (NAD kinases) are essential and ubiquitous enzymes involved in the production of NADP(H) which is an essential cofactor in many metabolic pathways. Targeting NAD kinase (NADK), a rate limiting enzyme of NADP biosynthesis pathway, represents a new promising a...

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Published in:European journal of medicinal chemistry 2023-01, Vol.246, p.114941-114941, Article 114941
Main Authors: Clément, David A., Gelin, Muriel, Leseigneur, Clarisse, Huteau, Valérie, Mondange, Lou, Pons, Jean-Luc, Dussurget, Olivier, Lionne, Corinne, Labesse, Gilles, Pochet, Sylvie
Format: Article
Language:English
Subjects:
Adenosine - pharmacology
Bacteria - metabolism
Biochemistry, Molecular Biology
Chemical Sciences
Crystal structure
Inhibitor
Life Sciences
Listeria
Macrocyclic compound
NAD kinase
NADP - metabolism
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Staphylococcus
Structural Biology
Structure-Activity Relationship
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Summary:Nicotinamide adenine dinucleotide kinases (NAD kinases) are essential and ubiquitous enzymes involved in the production of NADP(H) which is an essential cofactor in many metabolic pathways. Targeting NAD kinase (NADK), a rate limiting enzyme of NADP biosynthesis pathway, represents a new promising approach to treat bacterial infections. Previously, we have produced the first NADK inhibitor active against staphylococcal infection. From this linear di-adenosine derivative, namely NKI1, we designed macrocyclic analogues. Here, we describe the synthesis and evaluation of an original series of cyclic diadenosine derivatives as NADK inhibitors of two pathogenic bacteria, Listeria monocytogenes and Staphylococcus aureus. The nature and length of the link between the two adenosine units were examined leading to sub-micromolar inhibitors of NADK1 from L. monocytogenes, including its most potent in vitro inhibitor reported so far (with a 300-fold improvement compared to NKI1). [Display omitted] •A series of original diadenosine-based macrocycles as NADK inhibitor were developed.•Cyclic compounds displayed higher NADK inhibitory potency than acyclic precursors.•Crystal structures explain the affinity gain by intramolecular interactions.•LmNADK1 inhibition by MC1 represents a 300-fold improvement in comparison to our lead NKI1.•High NADK inhibitory potency of macrocycles was not translated into antibacterial activity.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2022.114941