Identification of 1,3-Diiminoisoindoline Carbohydrazides as Potential Antimalarial Candidates

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 IC50 value <100 nM. Synthesis of a variety of derivatives allowed an improvement of the initial antimalarial activity down to IC50=18 nM for the most potent compound, the establishment of a structureactivity 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 ligandiron(III) complexes, which also display antimalarial activity in the nanomolar IC50 range, paired with low cytotoxicity.