Potent naphthoquinones against antimony-sensitive and -resistant Leishmania parasites: synthesis of novel α- and nor-α-lapachone-based 1,2,3-triazoles by copper-catalyzed azide-alkyne cycloaddition

Eur J Med Chem. 2013 May:63:523-30. doi: 10.1016/j.ejmech.2013.02.038. Epub 2013 Mar 7.

Abstract

Continuing our screening program for novel anti-parasite compounds, we synthesized seven 1,4-naphthoquinones coupled to 1,2,3-triazoles, five nor-β-lapachone-based 1,2,3-triazoles and ten α-lapachone-based 1,2,3-triazoles. These and other naphthoquinonoid compounds were evaluated for their activity against promastigote forms of antimony-sensitive and -resistant strains of Leishmania infantum (syn. Leishmania chagasi) and Leishmania amazonensis. The toxicity of these compounds to mammalian cells was also examined. The substances were more potent than an antimonial drug, with IC50 values ranging from 1.0 to 50.7 μM. Nor-α-lapachone derivatives showed the highest antileishmanial activity, with selectivity indices in the range of 10-15. These compounds emerged as important leads for further investigation as antileishmanial agents. Additionally, one of these compounds exhibited cross-resistance in Sb-resistant Leishmania and could provide a molecular tool for investigating the multidrug resistance mechanisms in Leishmania parasites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes / chemistry
  • Animals
  • Antimony / pharmacology
  • Antiprotozoal Agents / chemical synthesis*
  • Antiprotozoal Agents / chemistry
  • Antiprotozoal Agents / pharmacology
  • Azides / chemistry
  • Catalysis
  • Cell Survival / drug effects
  • Cells, Cultured
  • Copper / chemistry
  • Cycloaddition Reaction / methods*
  • Drug Resistance / drug effects
  • Leishmania / drug effects
  • Leishmania infantum / drug effects
  • Macrophages, Peritoneal / cytology
  • Macrophages, Peritoneal / drug effects
  • Mice
  • Naphthoquinones / chemical synthesis*
  • Naphthoquinones / chemistry
  • Naphthoquinones / pharmacology
  • Parasitic Sensitivity Tests
  • Species Specificity
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • Alkynes
  • Antiprotozoal Agents
  • Azides
  • Naphthoquinones
  • Triazoles
  • Copper
  • Antimony
  • alpha-lapachone