Optimization Strategy of Novel Peptide-Based Michael Acceptors for the Treatment of Human African Trypanosomiasis

J Med Chem. 2019 Dec 12;62(23):10617-10629. doi: 10.1021/acs.jmedchem.9b00908. Epub 2019 Nov 27.

Abstract

This paper describes an optimization strategy of the highly active vinyl ketone 3 which was recognized as a strong inhibitor of rhodesain of Trypanosoma brucei rhodesiense, endowed with a ksecond value of 67 × 106 M-1 min-1 coupled with a high binding affinity (Ki = 38 pM). We now report a new structure-activity relationship study based on structural variations on the P3, P2, and P1' sites which led us to identify two potent lead compounds, i.e., vinyl ketones 4h and 4k. Vinyl ketone 4h showed an impressive potency toward rhodesain (ksecond = 8811 × 105) coupled to a good antiparasitic activity (EC50 = 3.6 μM), while vinyl ketone 4k proved to possess the highest binding affinity toward the trypanosomal protease (Ki = 0.6 pM) and a submicromolar antiparasitic activity (EC50 = 0.67 μM), thus representing new lead compounds in the drug discovery process for the treatment of Human African Trypanosomiasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cysteine Endopeptidases / metabolism*
  • Humans
  • Molecular Structure
  • Protein Conformation
  • Structure-Activity Relationship
  • Sulfones / chemistry
  • Sulfones / pharmacology
  • Trypanocidal Agents / chemistry*
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma brucei rhodesiense / drug effects*
  • Trypanosoma brucei rhodesiense / metabolism
  • Trypanosomiasis, African / drug therapy*

Substances

  • Sulfones
  • Trypanocidal Agents
  • Cysteine Endopeptidases
  • rhodesain