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Identification of 1,3‐Diiminoisoindoline Carbohydrazides as Potential Antimalarial Candidates
Author(s) -
Mombelli Paolo,
Witschel Matthias C.,
van Zijl Anthoni W.,
Geist Julie G.,
Rottmann Matthias,
Freymond Céline,
Röhl Franz,
Kaiser Marcel,
Illarionova Victoria,
Fischer Markus,
Siepe Isabella,
Schweizer W. Bernd,
Brun Reto,
Diederich François
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100441
Subject(s) - plasmodium falciparum , cytotoxicity , chemistry , stereochemistry , combinatorial chemistry , enzyme , ligand (biochemistry) , pharmacology , biochemistry , malaria , biology , in vitro , receptor , immunology
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 n M . Synthesis of a variety of derivatives allowed an improvement of the initial antimalarial activity down to IC 50 =18 n M 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.