Synthesis of macrocyclic trypanosomal cysteine protease inhibitors

Bioorg Med Chem Lett. 2008 Nov 15;18(22):5860-3. doi: 10.1016/j.bmcl.2008.06.012. Epub 2008 Jun 10.

Abstract

The importance of cysteine proteases in parasites, compounded with the lack of redundancy compared to their mammalian hosts makes proteases attractive targets for the development of new therapeutic agents. The binding mode of K11002 to cruzain, the major cysteine protease of Trypanosoma cruzi was used in the design of conformationally constrained inhibitors. Vinyl sulfone-containing macrocycles were synthesized via olefin ring-closing metathesis and evaluated against cruzain and the closely related cysteine protease, rhodesain.

Publication types

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

MeSH terms

  • Animals
  • Cysteine Endopeptidases / drug effects
  • Cysteine Proteinase Inhibitors / chemical synthesis*
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Dipeptides / chemistry
  • Dipeptides / pharmacology*
  • Drug Design
  • Molecular Structure
  • Protozoan Proteins / antagonists & inhibitors*
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry
  • Sulfones / pharmacology*
  • Trypanocidal Agents / chemical synthesis*
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma cruzi / enzymology*
  • Vinyl Compounds / chemical synthesis*
  • Vinyl Compounds / chemistry
  • Vinyl Compounds / pharmacology*

Substances

  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • N-pip-phenylalanine-homophenylalanine-vinyl sulfone phenyl
  • Protozoan Proteins
  • Sulfones
  • Trypanocidal Agents
  • Vinyl Compounds
  • morpholin- urea-phenylalanyl-homophenylalanyl-vinylsulfone-phenyl
  • Cysteine Endopeptidases
  • cruzain, Trypanosoma cruzi
  • rhodesain