1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors

摘要

A series of TMPK ( TMPK) inhibitors based on a reported compound were synthesized and evaluated for their capacity to inhibit TMPK catalytic activity and the growth of a virulent strain (H37Rv). Modifications of the scaffold of failed to afford substantial improvements in TMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of resulted in compound with improved TMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of to the -position afforded isomer , which, despite a 10-fold increase in IC -value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 μM).