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- Title
1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors.
- Authors
Jian, Yanlin; Hulpia, Fabian; D. P. Risseeuw, Martijn; Forbes, He Eun; Caljon, Guy; Munier-Lehmann, Hélène; I. M. Boshoff, Helena; Van Calenbergh, Serge; Geronikaki, Athina
- Abstract
A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold of 3 failed to afford substantial improvements in MtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of 3 resulted in compound 21j with improved MtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of 21j to the para-position afforded isomer 21h, which, despite a 10-fold increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 μM).
- Subjects
MYCOBACTERIUM tuberculosis; CATALYTIC activity; TUBERCULOSIS; ISOMERS
- Publication
Molecules, 2020, Vol 25, Issue 12, p2805
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules25122805