5-Substituted 3-chlorokenpaullone derivatives are potent inhibitors of Trypanosoma brucei bloodstream forms

Bioorg Med Chem. 2016 Aug 15;24(16):3790-800. doi: 10.1016/j.bmc.2016.06.023. Epub 2016 Jun 13.

Abstract

Trypanothione synthetase is an essential enzyme for kinetoplastid parasites which cause highly disabling and fatal diseases in humans and animals. Inspired by the observation that N(5)-substituted paullones inhibit the trypanothione synthetase from the related parasite Leishmania infantum, we designed and synthesized a series of new derivatives. Although none of the new compounds displayed strong inhibition of Trypanosoma brucei trypanothione synthetase, several of them caused a remarkable growth inhibition of cultivated Trypanosoma brucei bloodstream forms. The most potent congener 3a showed antitrypanosomal activity in double digit nanomolar concentrations and a selectivity index of three orders of magnitude versus murine macrophage cells.

Keywords: Leishmaniasis; Neglected tropical diseases; Paullone; Trypanosoma brucei; Trypanosomiasis; Trypanothione synthetase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amide Synthases / antagonists & inhibitors
  • Animals
  • Antiprotozoal Agents / chemistry
  • Antiprotozoal Agents / pharmacology*
  • Benzazepines / chemistry
  • Benzazepines / pharmacology*
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Spectrum Analysis / methods
  • Trypanosoma brucei brucei / drug effects*
  • Trypanosoma brucei brucei / enzymology

Substances

  • Antiprotozoal Agents
  • Benzazepines
  • Indoles
  • N-benzyl-2-(9-bromo-3-chloro-6-oxo-5,6,7,12-tetrahydrobenzo(2,3)azepino(4,5-b)indole-5-yl)acetamide
  • Amide Synthases
  • trypanothione synthetase