Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents.
Eur J Med Chem
; 201: 112450, 2020 Sep 01.
Article
in En
| MEDLINE
| ID: mdl-32623208
ABSTRACT
Mycobacterium tuberculosis, the causative agent of tuberculosis, relies on thymidylate kinase (MtbTMPK) for the synthesis of thymidine triphosphates and thus also DNA synthesis. Therefore, this enzyme constitutes a potential Achilles heel of the pathogen. Based on a previously reported MtbTMPK 6-aryl-substituted pyridone inhibitor and guided by two co-crystal structures of MtbTMPK with pyridone- and thymine-based inhibitors, we report the synthesis of a series of aryl-shifted cyanopyridone analogues. These compounds generally lacked significant MtbTMPK inhibitory potency, but some analogues did exhibit promising antitubercular activity. Analogue 11i demonstrated a 10-fold increased antitubercular activity (MIC H37Rv, 1.2 µM) compared to literature compound 5. Many analogues with whole-cell antimycobacterial activity were devoid of significant cytotoxicity.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyridones
/
Bacterial Proteins
/
Nucleoside-Phosphate Kinase
/
Enzyme Inhibitors
/
Nitriles
/
Antitubercular Agents
Language:
En
Journal:
Eur J Med Chem
Year:
2020
Document type:
Article
Affiliation country:
Bélgica
Publication country:
FR
/
FRANCE
/
FRANCIA
/
FRANÇA