2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of Plasmodium falciparum

The malaria parasite harbors a relict plastid called the apicoplast. Although not photosynthetic, the apicoplast retains unusual, non-mammalian metabolic pathways that are essential to the parasite, opening up a new perspective for the development of novel antimalarials which display a new mechanism...

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Published in:Pharmaceuticals (Basel, Switzerland) Switzerland), 2021-07, Vol.14 (8), p.724
Main Authors: Amrane, Dyhia, Arnold, Christophe-Sébastien, Hutter, Sébastien, Sanz-Serrano, Julen, Collia, Miguel, Azqueta, Amaya, Paloque, Lucie, Cohen, Anita, Amanzougaghene, Nadia, Tajeri, Shahin, Franetich, Jean-François, Mazier, Dominique, Benoit-Vical, Françoise, Verhaeghe, Pierre, Azas, Nadine, Vanelle, Patrice, Botté, Cyrille, Primas, Nicolas
Format: Article
Language:English
Subjects:
Antibiotics
apicoplast
Biosynthesis
Chemical Sciences
Cytotoxicity
Drugs
Human health and pathology
Infectious diseases
Life Sciences
Malaria
Medicinal Chemistry
Parasites
Parasitic diseases
Pharmaceutical sciences
Pharmacology
Phenols
Plasmodium falciparum
quinoxaline
structure-activity relationships
Sulfur
trichloromethyl goup
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Summary:The malaria parasite harbors a relict plastid called the apicoplast. Although not photosynthetic, the apicoplast retains unusual, non-mammalian metabolic pathways that are essential to the parasite, opening up a new perspective for the development of novel antimalarials which display a new mechanism of action. Based on the previous antiplasmodial hit-molecules identified in the 2-trichloromethylquinoxaline series, we report herein a structure–activity relationship (SAR) study at position two of the quinoxaline ring by synthesizing 20 new compounds. The biological evaluation highlighted a hit compound (3i) with a potent PfK1 EC50 value of 0.2 µM and a HepG2 CC50 value of 32 µM (Selectivity index = 160). Nitro-containing (3i) was not genotoxic, both in the Ames test and in vitro comet assay. Activity cliffs were observed when the 2-CCl3 group was replaced, showing that it played a key role in the antiplasmodial activity. Investigation of the mechanism of action showed that 3i presents a drug response by targeting the apicoplast and a quick-killing mechanism acting on another target site.
ISSN:1424-8247
1424-8247
DOI:10.3390/ph14080724