Structural Insights into the Development of Cycloguanil Derivatives as Trypanosoma brucei Pteridine-Reductase-1 Inhibitors

ACS Infect Dis. 2019 Jul 12;5(7):1105-1114. doi: 10.1021/acsinfecdis.8b00358. Epub 2019 May 1.

Abstract

Cycloguanil is a known dihydrofolate-reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of Trypanosoma brucei PTR1 (TbPTR1). A small library of cycloguanil derivatives was developed, resulting in 1 and 2a having IC50 values of 692 and 186 nM, respectively, toward TbPTR1. Structural analysis revealed that the increased potency of 1 and 2a is due to the combined contributions of hydrophobic interactions, H-bonds, and halogen bonds. Moreover, in vitro cell-growth-inhibition tests indicated that 2a is also effective on T. brucei. The simultaneous inhibition of DHFR and PTR1 activity in T. brucei is a promising new strategy for the treatment of human African trypanosomiasis. For this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.

Keywords: antiparasite drugs; cycloguanil; folate pathway; pteridine reductase; triazine derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Molecular Structure
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / chemistry
  • Proguanil / chemistry*
  • Proguanil / pharmacology
  • Protozoan Proteins / antagonists & inhibitors
  • Protozoan Proteins / chemistry
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship
  • Triazines / chemical synthesis*
  • Triazines / chemistry
  • Triazines / pharmacology
  • Trypanocidal Agents / chemical synthesis*
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology
  • Trypanosoma brucei brucei / drug effects
  • Trypanosoma brucei brucei / enzymology*

Substances

  • Enzyme Inhibitors
  • Protozoan Proteins
  • Small Molecule Libraries
  • Triazines
  • Trypanocidal Agents
  • cycloguanil
  • Oxidoreductases
  • pteridine reductase
  • Proguanil