Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors

PLoS Negl Trop Dis. 2015 Jul 14;9(7):e0003916. doi: 10.1371/journal.pntd.0003916. eCollection 2015.

Abstract

A series of compounds based on the dipeptidyl nitrile scaffold were synthesized and assayed for their inhibitory activity against the T. cruzi cysteine protease cruzain. Structure activity relationships (SARs) were established using three, eleven and twelve variations respectively at the P1, P2 and P3 positions. A Ki value of 16 nM was observed for the most potent of these inhibitors which reflects a degree of non-additivity in the SAR. An X-ray crystal structure was determined for the ligand-protein complex for the structural prototype for the series. Twenty three inhibitors were also evaluated for their anti-trypanosomal effects and an EC50 value of 28 μM was observed for the most potent of these. Although there remains scope for further optimization, the knowledge gained from this study is also transferable to the design of cruzain inhibitors based on warheads other than nitrile as well as alternative scaffolds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Chagas Disease / drug therapy
  • Chagas Disease / parasitology*
  • Crystallography, X-Ray
  • Cysteine Endopeptidases / chemistry
  • Cysteine Endopeptidases / metabolism
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Kinetics
  • Nitriles / chemistry
  • Nitriles / pharmacology
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / metabolism
  • Structure-Activity Relationship
  • Trypanocidal Agents / chemical synthesis*
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma cruzi / drug effects*
  • Trypanosoma cruzi / enzymology

Substances

  • Enzyme Inhibitors
  • Nitriles
  • Protozoan Proteins
  • Trypanocidal Agents
  • Cysteine Endopeptidases
  • cruzain, Trypanosoma cruzi

Grants and funding

Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) through the granting award number 2013/18009-4, which can be accessed at http://internet.aquila.fapesp.br/agilis/publico/, provided funding to carry out this work. We are also indebted to Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) for providing the grant from project number 301614/2010-5 (www.cnpq.br). In addition, CAPES and CNPq are also acknowledged for providing scholarships. The sponsors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.