2 H-1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Trypanocidal Rhodesain Inhibitors by Structure-Based Design

J Med Chem. 2018 Apr 26;61(8):3370-3388. doi: 10.1021/acs.jmedchem.7b01870. Epub 2018 Apr 6.

Abstract

Macrocyclic inhibitors of rhodesain (RD), a parasitic cysteine protease and drug target for the treatment of human African trypanosomiasis, have shown low metabolic stability at the macrocyclic ether bridge. A series of acyclic dipeptidyl nitriles was developed using structure-based design (PDB ID: 6EX8 ). The selectivity against the closely related cysteine protease human cathepsin L (hCatL) was substantially improved, up to 507-fold. In the S2 pocket, 3,4-dichlorophenylalanine residues provided high trypanocidal activities. In the S3 pocket, aromatic residues provided enhanced selectivity against hCatL. RD inhibition ( Ki values) and in vitro cell-growth of Trypanosoma brucei rhodesiense (IC50 values) were measured in the nanomolar range. Triazole-based ligands, obtained by a safe, gram-scale flow production of ethyl 1 H-1,2,3-triazole-4-carboxylate, showed excellent metabolic stability in human liver microsomes and in vivo half-lives of up to 1.53 h in mice. When orally administered to infected mice, parasitaemia was reduced but without complete removal of the parasites.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Binding Sites
  • Cell Line
  • Cysteine Endopeptidases / chemistry
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / pharmacokinetics
  • Cysteine Proteinase Inhibitors / therapeutic use*
  • Cysteine Proteinase Inhibitors / toxicity
  • Dipeptides / chemical synthesis
  • Dipeptides / pharmacokinetics
  • Dipeptides / therapeutic use*
  • Dipeptides / toxicity
  • Drug Design
  • Female
  • Humans
  • Leishmania donovani / drug effects
  • Ligands
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Nitriles / chemical synthesis
  • Nitriles / pharmacokinetics
  • Nitriles / therapeutic use*
  • Nitriles / toxicity
  • Plasmodium falciparum / drug effects
  • Protozoan Proteins / antagonists & inhibitors
  • Protozoan Proteins / chemistry
  • Rats
  • Structure-Activity Relationship
  • Swine
  • Triazoles / chemical synthesis
  • Triazoles / pharmacokinetics
  • Triazoles / therapeutic use*
  • Triazoles / toxicity
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / pharmacokinetics
  • Trypanocidal Agents / therapeutic use*
  • Trypanocidal Agents / toxicity
  • Trypanosoma brucei rhodesiense / drug effects
  • Trypanosoma cruzi / drug effects

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • Ligands
  • Nitriles
  • Protozoan Proteins
  • Triazoles
  • Trypanocidal Agents
  • Cysteine Endopeptidases
  • rhodesain