Development of novel dipeptide nitriles as inhibitors of rhodesain of Trypanosoma brucei rhodesiense

Eur J Med Chem. 2022 Jun 5:236:114328. doi: 10.1016/j.ejmech.2022.114328. Epub 2022 Mar 29.

Abstract

In this paper, we developed a new series of dipeptide nitriles that were demonstrated to be reversible rhodesain inhibitors at nanomolar level, with EC50 values against cultured T. b. brucei in the micromolar range. We also proved that our dipeptide nitriles directly bind to the active site of rhodesain acting as competitive inhibitors. Within the most interesting compounds, the dipeptide nitrile 2b showed the highest binding affinity towards rhodesain (Ki = 16 nM) coupled with a good antiparasitic activity (EC50 = 14.1 μM). Moreover, for the dipeptide nitrile 3e, which showed a Ki = 122 nM towards the trypanosomal protease, we obtained the highest antiparasitic activity (EC50 = 8.8 μM). Thus, given the obtained results both compounds could certainly represent new lead compounds for the discovery of new drugs to treat Human African Trypanosomiasis.

Keywords: Antitrypanosomal agents; Cysteine protease; Dipeptide nitriles; Docking studies; Rhodesain inhibitors.

MeSH terms

  • Cysteine Endopeptidases
  • Cysteine Proteinase Inhibitors* / chemistry
  • Cysteine Proteinase Inhibitors* / pharmacology
  • Dipeptides* / chemistry
  • Dipeptides* / pharmacology
  • Nitriles* / chemistry
  • Nitriles* / pharmacology
  • Structure-Activity Relationship
  • Trypanocidal Agents* / chemistry
  • Trypanocidal Agents* / pharmacology
  • Trypanosoma brucei rhodesiense* / drug effects

Substances

  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • Nitriles
  • Trypanocidal Agents
  • Cysteine Endopeptidases
  • rhodesain