Catechol pyrazolinones as trypanocidals: fragment-based design, synthesis, and pharmacological evaluation of nanomolar inhibitors of trypanosomal phosphodiesterase B1

J Med Chem. 2012 Oct 25;55(20):8745-56. doi: 10.1021/jm301059b. Epub 2012 Oct 8.

Abstract

Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modeling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC₅₀ values down to 49 nM. The compounds also block parasite proliferation (e.g., VUF13525 (20b): T. brucei rhodesiense IC₅₀ = 60 nM, T. brucei brucei IC₅₀ = 520 nM, T. cruzi = 7.6 μM), inducing a typical multiple nuclei and kinetoplast phenotype without being generally cytotoxic. The mode of action of 20b was investigated with recombinantly engineered trypanosomes expressing a cAMP-sensitive FRET sensor, confirming a dose-response related increase of intracellular cAMP levels in trypanosomes. Our findings further validate the TbrPDEB family as antitrypanosomal target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catechols / chemical synthesis*
  • Catechols / chemistry
  • Catechols / pharmacology
  • Cyclic AMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 1 / antagonists & inhibitors*
  • Cyclic Nucleotide Phosphodiesterases, Type 1 / chemistry
  • Drug Design
  • Molecular Docking Simulation
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Pyrazolones / chemical synthesis*
  • Pyrazolones / chemistry
  • Pyrazolones / pharmacology
  • Structure-Activity Relationship
  • Tetrazoles / chemical synthesis*
  • Tetrazoles / chemistry
  • Tetrazoles / pharmacology
  • Trypanocidal Agents / chemical synthesis*
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology
  • Trypanosoma brucei brucei / drug effects*
  • Trypanosoma brucei brucei / enzymology
  • Trypanosoma brucei rhodesiense / drug effects
  • Trypanosoma brucei rhodesiense / enzymology

Substances

  • 3-(3-(4-(4-(2H-tetrazole-5-yl)phenoxy)butoxy)-4-methoxyphenyl)-1-cycloheptyl-4,4-dimethyl-1H-pyrazol-5(4H)-one
  • Catechols
  • Pyrazoles
  • Pyrazolones
  • Tetrazoles
  • Trypanocidal Agents
  • Cyclic AMP
  • Cyclic Nucleotide Phosphodiesterases, Type 1