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

Graphical Abstract

Antiprotozoals from herbicides: A library screen revealed a 1,3-diiminoisoindoline carbohydrazide derivative to be a potent inhibitor of the in vitro proliferation of P. falciparum in red blood cells. A variety of derivatives, including Fe^III complexes, were synthesized and displayed antimalarial activity down to the double-digit nanomolar IC₅₀ range.

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 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 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 IC₅₀ range, paired with low cytotoxicity.