Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors.
Antitubercular Agents
/ chemical synthesis
Dose-Response Relationship, Drug
Enzyme Inhibitors
/ chemical synthesis
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis
/ drug effects
Nucleoside-Phosphate Kinase
/ antagonists & inhibitors
Piperidines
/ chemical synthesis
Structure-Activity Relationship
Thymine
/ chemical synthesis
Mycobacterium tuberculosis
Structure-based inhibitor design
Thymidylate kinase
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:
05 Dec 2021
05 Dec 2021
Historique:
received:
30
04
2021
revised:
14
08
2021
accepted:
14
08
2021
pubmed:
28
8
2021
medline:
14
1
2022
entrez:
27
8
2021
Statut:
ppublish
Résumé
Mycobacterium tuberculosis thymidylate kinase (MtTMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside MtTMPK inhibitors in an effort to diversify MtTMPK inhibitor chemical space. We here report a new series of MtTMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of MtTMPK in complex with developed inhibitors. These efforts furnished the most potent MtTMPK inhibitors in our assay, with two analogues displaying low micromolar MIC values against H37Rv Mtb. Prepared inhibitors address new sub-sites in the MtTMPK nucleotide binding pocket, thereby offering new insights into its druggability. We studied the role of efflux pumps as well as the impact of cell wall permeabilizers for selected compounds to potentially provide an explanation for the lack of correlation between potent enzyme inhibition and whole-cell activity.
Identifiants
pubmed: 34450493
pii: S0223-5234(21)00633-4
doi: 10.1016/j.ejmech.2021.113784
pmc: PMC10500704
mid: NIHMS1929503
pii:
doi:
Substances chimiques
Antitubercular Agents
0
Enzyme Inhibitors
0
Piperidines
0
piperidine
67I85E138Y
Nucleoside-Phosphate Kinase
EC 2.7.4.4
dTMP kinase
EC 2.7.4.9
Thymine
QR26YLT7LT
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
113784Subventions
Organisme : Intramural NIH HHS
ID : Z99 AI999999
Pays : United States
Informations de copyright
Copyright © 2021 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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