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

• Main Authors: Dyhia Amrane, Christophe-Sébastien Arnold, Sébastien Hutter, Julen Sanz-Serrano, Miguel Collia, Amaya Azqueta, Lucie Paloque, Anita Cohen, Nadia Amanzougaghene, Shahin Tajeri, Jean-François Franetich, Dominique Mazier, Françoise Benoit-Vical, Pierre Verhaeghe, Nadine Azas, Patrice Vanelle, Cyrille Botté, Nicolas Primas
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: Pharmaceuticals
• Subjects: quinoxaline; trichloromethyl goup; <i>Plasmodium falciparum</i>; structure-activity relationships; apicoplast
• Online Access: https://www.mdpi.com/1424-8247/14/8/724

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 (<b>3i</b>) with a potent <i>Pf</i>K1 EC₅₀ value of 0.2 µM and a HepG2 CC₅₀ value of 32 µM (Selectivity index = 160). Nitro-containing (<b>3i</b>) 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 <b>3i</b> presents a drug response by targeting the apicoplast and a quick-killing mechanism acting on another target site.