2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of <i>Plasmodium falciparum</i>
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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doaj-5dd08eb5d7524519bd2a427e208e30202021-08-26T14:12:08ZengMDPI AGPharmaceuticals1424-82472021-07-011472472410.3390/ph140807242-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of <i>Plasmodium falciparum</i>Dyhia Amrane0Christophe-Sébastien Arnold1Sébastien Hutter2Julen Sanz-Serrano3Miguel Collia4Amaya Azqueta5Lucie Paloque6Anita Cohen7Nadia Amanzougaghene8Shahin Tajeri9Jean-François Franetich10Dominique Mazier11Françoise Benoit-Vical12Pierre Verhaeghe13Nadine Azas14Patrice Vanelle15Cyrille Botté16Nicolas Primas17Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, CEDEX 05, 13385 Marseille, FranceApicoLipid Team, Institute for Advanced Biosciences, Université Grenoble Alpes, 38700 La Tronche, FranceAix Marseille Univ, IHU Méditerranée Infection, UMR VITROME, IRD, SSA, Mycology & Tropical Eucaryotic Pathogens, CEDEX 05, 13005 Marseille, FranceDepartment of Pharmacology and Toxicology, Faculty of Pharmacy and Nutrition, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, SpainDepartment of Pharmacology and Toxicology, Faculty of Pharmacy and Nutrition, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, SpainDepartment of Pharmacology and Toxicology, Faculty of Pharmacy and Nutrition, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, SpainLCC-CNRS, Université de Toulouse, CNRS UPR8241, UPS, 31400 Toulouse, FranceAix Marseille Univ, IHU Méditerranée Infection, UMR VITROME, IRD, SSA, Mycology & Tropical Eucaryotic Pathogens, CEDEX 05, 13005 Marseille, FranceSorbonne Université, INSERM, CNRS, Centre d’Immunologie et des Maladies Infectieuses, CIMI, 75013 Paris, FranceSorbonne Université, INSERM, CNRS, Centre d’Immunologie et des Maladies Infectieuses, CIMI, 75013 Paris, FranceSorbonne Université, INSERM, CNRS, Centre d’Immunologie et des Maladies Infectieuses, CIMI, 75013 Paris, FranceSorbonne Université, INSERM, CNRS, Centre d’Immunologie et des Maladies Infectieuses, CIMI, 75013 Paris, FranceLCC-CNRS, Université de Toulouse, CNRS UPR8241, UPS, 31400 Toulouse, FranceLCC-CNRS, Université de Toulouse, CNRS UPR8241, UPS, 31400 Toulouse, FranceAix Marseille Univ, IHU Méditerranée Infection, UMR VITROME, IRD, SSA, Mycology & Tropical Eucaryotic Pathogens, CEDEX 05, 13005 Marseille, FranceAix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, CEDEX 05, 13385 Marseille, FranceApicoLipid Team, Institute for Advanced Biosciences, Université Grenoble Alpes, 38700 La Tronche, FranceAix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, CEDEX 05, 13385 Marseille, FranceThe 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 EC<sub>50</sub> value of 0.2 µM and a HepG2 CC<sub>50</sub> 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-CCl<sub>3</sub> 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.https://www.mdpi.com/1424-8247/14/8/724quinoxalinetrichloromethyl goup<i>Plasmodium falciparum</i>structure-activity relationshipsapicoplast |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of <i>Plasmodium falciparum</i> Pharmaceuticals quinoxaline trichloromethyl goup <i>Plasmodium falciparum</i> structure-activity relationships apicoplast |
author_facet |
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 |
author_sort |
Dyhia Amrane |
title |
2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of <i>Plasmodium falciparum</i> |
title_short |
2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of <i>Plasmodium falciparum</i> |
title_full |
2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of <i>Plasmodium falciparum</i> |
title_fullStr |
2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of <i>Plasmodium falciparum</i> |
title_full_unstemmed |
2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of <i>Plasmodium falciparum</i> |
title_sort |
2-phenoxy-3-trichloromethylquinoxalines are antiplasmodial derivatives with activity against the apicoplast of <i>plasmodium falciparum</i> |
publisher |
MDPI AG |
series |
Pharmaceuticals |
issn |
1424-8247 |
publishDate |
2021-07-01 |
description |
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 EC<sub>50</sub> value of 0.2 µM and a HepG2 CC<sub>50</sub> 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-CCl<sub>3</sub> 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. |
topic |
quinoxaline trichloromethyl goup <i>Plasmodium falciparum</i> structure-activity relationships apicoplast |
url |
https://www.mdpi.com/1424-8247/14/8/724 |
work_keys_str_mv |
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