Synthesis and assessment of catechol diether compounds as inhibitors of trypanosomal phosphodiesterase B1 (TbrPDEB1)

Bioorg Med Chem Lett. 2013 Nov 1;23(21):5971-4. doi: 10.1016/j.bmcl.2013.08.057. Epub 2013 Aug 21.

Abstract

Human African trypanosomiasis (HAT) is a parasitic neglected tropical disease that affects 10,000 patients each year. Current treatments are sub-optimal, and the disease is fatal if not treated. Herein, we report our continuing efforts to repurpose the human phosphodiesterase 4 (hPDE4) inhibitor piclamilast to target trypanosomal phosphodiesterase TbrPDEB1. We prepared a range of substituted heterocyclic replacements for the 4-amino-3,5-dichloro-pyridine headgroup of piclamilast, and found that these compounds exhibited weak inhibitory activity of TbrPDEB1.

Keywords: Drug discovery; Neglected Disease; Phosphodiesterases; Piclamilast; TbrPDEB1; TbrPDEB2; Trypanosoma brucei.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Catechols / chemistry*
  • Catechols / pharmacology*
  • Drug Discovery
  • Humans
  • Models, Molecular
  • Phosphodiesterase 4 Inhibitors / chemistry
  • Phosphodiesterase 4 Inhibitors / pharmacology
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / metabolism
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Trypanocidal Agents / chemistry*
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma brucei brucei / drug effects*
  • Trypanosoma brucei brucei / enzymology
  • Trypanosomiasis, African / drug therapy
  • Trypanosomiasis, African / parasitology

Substances

  • Benzamides
  • Catechols
  • Phosphodiesterase 4 Inhibitors
  • Protozoan Proteins
  • Pyridines
  • Trypanocidal Agents
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • PDEB1 protein, Trypanosoma brucei
  • catechol
  • piclamilast