Identification of 1,3-diiminoisoindoline carbohydrazides as potential antimalarial candidates

ChemMedChem. 2012 Jan 2;7(1):151-8. doi: 10.1002/cmdc.201100441. Epub 2011 Nov 16.

Abstract

A series of inhibitors of plant enzymes of the non-mevalonate pathway from herbicide research efforts at BASF were screened for antimalarial activity in a cell-based assay. A 1,3-diiminoisoindoline carbohydrazide was found to inhibit the growth of Plasmodium falciparum with an IC(50) value <100 nM. Synthesis of a variety of derivatives allowed an improvement of the initial antimalarial activity down to IC(50) =18 nM for the most potent compound, the establishment of a structure-activity relationship, and the evaluation of the cytotoxic profile of the diiminoisoindolines. Furthermore, interesting configurational and conformational aspects for this class of compounds were studied by computational and X-ray crystal structure analysis. Some of the compounds can act as tridentate ligands, forming 2:1 ligand-iron(III) complexes, which also display antimalarial activity in the nanomolar IC(50) range, paired with low cytotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemistry*
  • Antimalarials / pharmacology*
  • Cell Line
  • Cell Survival / drug effects
  • Humans
  • Hydrazines / chemistry*
  • Hydrazines / pharmacology*
  • Isoindoles / chemistry*
  • Isoindoles / pharmacology*
  • Malaria, Falciparum / drug therapy
  • Plasmodium falciparum / drug effects*
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Hydrazines
  • Isoindoles
  • carbohydrazide