Elaboration of a proprietary thymidylate kinase inhibitor motif towards anti-tuberculosis agents.
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.
Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteemweg 460, B-9000 Ghent, Belgium.
Lijun
L
Song
Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteemweg 460, B-9000 Ghent, Belgium.
Martijn D P
MDP
Risseeuw
Medicinal Chemistry (Rega Institute), Department of Pharmaceutical and Pharmacological Sciences, KU LEUVEN, Minderbroedersstraat 10 blok x-box 1030, 3000 Leuven, Belgium.
Matheus
M
Froeyen
Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteemweg 460, B-9000 Ghent, Belgium.
Izet
I
Karalic
Laboratory for Organic and Bioorganic Synthesis, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281, S4, B-9000 Ghent, Belgium.
Jan
J
Goeman
Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Department of Pharmaceutical Sciences, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, B-2610 Antwerpen,. Belgium.
Davie
D
Cappoen
Laboratory for Organic and Bioorganic Synthesis, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281, S4, B-9000 Ghent, Belgium.
Johan
J
Van der Eycken
Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Department of Pharmaceutical Sciences, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, B-2610 Antwerpen,. Belgium.
Paul
P
Cos
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.
Hélène
H
Munier-Lehmann
Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteemweg 460, B-9000 Ghent, Belgium. Electronic address: serge.vancalenbergh@ugent.be.
Serge
S
Van Calenbergh
D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000995:Antitubercular Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C032727:piperidine; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase
Inhibitors; Mycobacterium tuberculosis; Thymidine monophosphate kinase; Thymine derivatives; XDR-TB; extensively drug-resistant tuberculosis