title: Identification of 1,3-diiminoisoindoline carbohydrazides as potential antimalarial candidates.
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.
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, Zürich, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mombelli
authors.forename: Matthias C
authors.initials: MC
authors.lastname: Witschel
authors.forename: Anthoni W
authors.initials: AW
authors.lastname: van Zijl
authors.forename: Julie G
authors.initials: JG
authors.lastname: Geist
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.forename: Céline
authors.initials: C
authors.lastname: Freymond
authors.forename: Franz
authors.initials: F
authors.lastname: Röhl
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Victoria
authors.initials: V
authors.lastname: Illarionova
authors.forename: Markus
authors.initials: M
authors.lastname: Fischer
authors.forename: Isabella
authors.initials: I
authors.lastname: Siepe
authors.forename: W Bernd
authors.initials: WB
authors.lastname: Schweizer
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: François
authors.initials: F
authors.lastname: Diederich
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology*; D054833:Isoindoles / Q000737:chemistry* / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D006834:Hydrazines; D054833:Isoindoles; C019289:carbohydrazide