1-(Piperidin-3-yl)thymine amides as inhibitors of M. tuberculosis thymidylate kinase

Yanlin Jian; Martijn D P Risseeuw; Mathy Froeyen; Lijun Song; Davie Cappoen; Paul Cos; Hélène Munier-Lehmann; Serge van Calenbergh

doi:10.1080/14756366.2019.1662790

1-(Piperidin-3-yl)thymine amides as inhibitors of M. tuberculosis thymidylate kinase

J Enzyme Inhib Med Chem. 2019 Dec;34(1):1730-1739. doi: 10.1080/14756366.2019.1662790.

Authors

Yanlin Jian¹, Martijn D P Risseeuw¹, Mathy Froeyen², Lijun Song¹, Davie Cappoen³, Paul Cos³, Hélène Munier-Lehmann⁴, Serge van Calenbergh¹

Affiliations

¹ Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
² Department of Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
³ Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium.
⁴ Unit of Chemistry and Biocatalysis, Department of Structural Biology and Chemistry, Institut Pasteur, CNRS UMR3523, Paris, France.

Abstract

A series of readily accessible 1-(piperidin-3-yl)thymine amides was designed, synthesised and evaluated as Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors. In line with the modelling results, most inhibitors showed reasonable MtbTMPK inhibitory activity. Compounds 4b and 4i were slightly more potent than the parent compound 3. Moreover, contrary to the latter, amide analogue 4g was active against the avirulent M. tuberculosis H37Ra strain (MIC₅₀=35 µM). This finding opens avenues for future modifications.

Keywords: Mycobacterium tuberculosis; Thymidylate kinase; inhibitors; modelling.

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Antitubercular Agents / chemical synthesis
Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / enzymology
Nucleoside-Phosphate Kinase / antagonists & inhibitors*
Nucleoside-Phosphate Kinase / metabolism
Structure-Activity Relationship
Thymine / chemical synthesis
Thymine / chemistry
Thymine / pharmacology*

Substances

Amides
Antitubercular Agents
Enzyme Inhibitors
Nucleoside-Phosphate Kinase
dTMP kinase
Thymine

Grants and funding

This work was supported by the China Scholarship Council (grant numbers 201607060021).