In vitro antiplasmodial activity of triazole-linked chloroquinoline derivatives synthesized from 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine

Bioorg Med Chem. 2015 Aug 1;23(15):4163-4171. doi: 10.1016/j.bmc.2015.06.044. Epub 2015 Jun 27.

Abstract

The synthesis and in vitro evaluation of novel triazole-linked chloroquinoline derivatives as potential antiplasmodial agents against Plasmodium falciparum is reported. The 15 synthesized target compounds were obtained by means of a copper(I)-mediated click reaction between a variety of 1,2- and 1,3-azidoamines and 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine in moderate to good yields (53-85%). The compounds were screened for antiplasmodial activity against NF54 chloroquine-sensitive and Dd2 chloroquine-resistant strains, alongside chloroquine and artesunate as reference compounds. Six of the test compounds revealed a 3-5 fold increase in antiplasmodial activity against chloroquine-resistant strain Dd2 compared to chloroquine. Among the six compounds with good antiplasmodial activity, a reduced cross-resistance relative to artesunate (>3 fold in comparison to chloroquine) was observed, mainly in derivatives that incorporated chloroquine-resistance reversing pharmacophores. A general trend for reduced chloroquine cross-resistance was also detected among 12 out of the 15 compounds tested.

Keywords: 4-Aminoquinoline; Antiplasmodial; CuAAC click chemistry; Resistance reversal; Triazole linkers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry*
  • Antimalarials / pharmacology*
  • Artemisinins / pharmacology
  • Artesunate
  • Chloroquine / chemistry*
  • Click Chemistry
  • Drug Evaluation, Preclinical / methods
  • Drug Resistance / drug effects
  • Molecular Structure
  • Plasmodium falciparum / drug effects*
  • Triazoles / chemistry*

Substances

  • Antimalarials
  • Artemisinins
  • Triazoles
  • Artesunate
  • Chloroquine