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

Molecules. 2020 Jun 17;25(12):2805. doi: 10.3390/molecules25122805.

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).

Keywords: 1-(1-arylethylpiperidin-4-yl)thymine; MtbTMPK; Mycobacterium tuberculosis; tuberculosis.

MeSH terms

  • Antitubercular Agents* / chemical synthesis
  • Antitubercular Agents* / chemistry
  • Antitubercular Agents* / pharmacology
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Mycobacterium tuberculosis / enzymology*
  • Nucleoside-Phosphate Kinase / antagonists & inhibitors*
  • Nucleoside-Phosphate Kinase / metabolism
  • Structure-Activity Relationship
  • Thymine* / analogs & derivatives
  • Thymine* / chemical synthesis
  • Thymine* / chemistry
  • Thymine* / pharmacology

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Nucleoside-Phosphate Kinase
  • dTMP kinase
  • Thymine