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

A series ofMycobacterium tuberculosisTMPK (MtbTMPK) inhibitors based on a reported compound3were synthesized and evaluated for their capacity to inhibitMtbTMPK catalytic activity and the growth of a virulentM. tuberculosisstrain (H37Rv). Modifications of the scaffold of3failed to afford substantial improvements inMtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of3resulted in compound21jwith improvedMtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of21jto thepara-position afforded isomer21h, which, despite a 10-fold increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 mu M).