Parallel synthesis of a library of 1,4-naphthoquinones and automated screening of potential inhibitors of trypanothione reductase from Trypanosoma cruzi

Bioorg Med Chem Lett. 2000 Apr 3;10(7):631-5. doi: 10.1016/s0960-894x(00)00056-1.

Abstract

Solid- and solution-phase parallel syntheses of 1,4-naphthoquinones (1,4-NQ) are described. A library of 1360 amides was constructed from the combination of 12 newly synthesised 1,4-NQ carboxylic acid and 120 amines, and was screened for inhibition of trypanothione reductase (TR) from Trypanosoma cruzi. The most active hits from a primary screening were re-synthesised and confirmed. This approach proves that it is possible to design potent and highly specific TcTR inhibitors deriving from menadione, juglone and plumbagin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiprotozoal Agents / chemical synthesis*
  • Antiprotozoal Agents / chemistry
  • Antiprotozoal Agents / pharmacology
  • Automation
  • Drug Evaluation, Preclinical / methods
  • Inhibitory Concentration 50
  • NADH, NADPH Oxidoreductases / antagonists & inhibitors*
  • Naphthoquinones / chemical synthesis*
  • Naphthoquinones / chemistry
  • Naphthoquinones / pharmacology
  • Quality Control
  • Trypanosoma cruzi / drug effects*
  • Trypanosoma cruzi / enzymology

Substances

  • Antiprotozoal Agents
  • Naphthoquinones
  • NADH, NADPH Oxidoreductases
  • trypanothione reductase
  • 1,4-naphthoquinone