Elaboration of a proprietary thymidylate kinase inhibitor motif towards anti-tuberculosis agents

Lijun Song; Martijn D P Risseeuw; Matheus Froeyen; Izet Karalic; Jan Goeman; Davie Cappoen; Johan Van der Eycken; Paul Cos; Hélène Munier-Lehmann; Serge Van Calenbergh

doi:10.1016/j.bmc.2016.08.041

Elaboration of a proprietary thymidylate kinase inhibitor motif towards anti-tuberculosis agents

Bioorg Med Chem. 2016 Nov 1;24(21):5172-5182. doi: 10.1016/j.bmc.2016.08.041. Epub 2016 Aug 24.

Authors

Affiliations

¹ Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteemweg 460, B-9000 Ghent, Belgium.
² Medicinal Chemistry (Rega Institute), Department of Pharmaceutical and Pharmacological Sciences, KU LEUVEN, Minderbroedersstraat 10 blok x-box 1030, 3000 Leuven, Belgium.
³ Laboratory for Organic and Bioorganic Synthesis, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281, S4, B-9000 Ghent, Belgium.
⁴ Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Department of Pharmaceutical Sciences, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, B-2610 Antwerpen,. Belgium.
⁵ Institut Pasteur, Unit of Chemistry and Biocatalysis, Department of Structural Biology and Chemistry, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France; CNRS UMR3523, Paris, France.
⁶ Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteemweg 460, B-9000 Ghent, Belgium. Electronic address: serge.vancalenbergh@ugent.be.

PMID: 27614917
DOI: 10.1016/j.bmc.2016.08.041

Abstract

We report the design and synthesis of a series of non-nucleoside MtbTMPK inhibitors (1-14) based on the gram-positive bacterial TMPK inhibitor hit compound 1. A practical synthesis was developed to access these analogues. Several compounds show promising MtbTMPK inhibitory potency and allow the establishment of a structure-activity relationship, which is helpful for further optimization.

Keywords: Inhibitors; Mycobacterium tuberculosis; Thymidine monophosphate kinase; Thymine derivatives; XDR-TB; extensively drug-resistant tuberculosis.

Publication types

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

MeSH terms

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

Substances

Antitubercular Agents
Piperidines
Protein Kinase Inhibitors
piperidine
Nucleoside-Phosphate Kinase
dTMP kinase