{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T22:12:36Z","timestamp":1790547156583,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T00:00:00Z","timestamp":1627257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-17-CE11-0017"],"award-info":[{"award-number":["ANR-17-CE11-0017"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["DCM20181039565"],"award-info":[{"award-number":["DCM20181039565"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>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\u2013activity 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 \u00b5M and a HepG2 CC50 value of 32 \u00b5M (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.<\/jats:p>","DOI":"10.3390\/ph14080724","type":"journal-article","created":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T22:22:46Z","timestamp":1627338166000},"page":"724","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of Plasmodium falciparum"],"prefix":"10.3390","volume":"14","author":[{"given":"Dyhia","family":"Amrane","sequence":"first","affiliation":[{"name":"Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Facult\u00e9 de Pharmacie, CEDEX 05, 13385 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2392-5837","authenticated-orcid":false,"given":"Christophe-S\u00e9bastien","family":"Arnold","sequence":"additional","affiliation":[{"name":"ApicoLipid Team, Institute for Advanced Biosciences, Universit\u00e9 Grenoble Alpes, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Hutter","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, IHU M\u00e9diterran\u00e9e Infection, UMR VITROME, IRD, SSA, Mycology & Tropical Eucaryotic Pathogens, CEDEX 05, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0503-2752","authenticated-orcid":false,"given":"Julen","family":"Sanz-Serrano","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy and Nutrition, University of Navarra, C\/Irunlarrea 1, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Collia","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy and Nutrition, University of Navarra, C\/Irunlarrea 1, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amaya","family":"Azqueta","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy and Nutrition, University of Navarra, C\/Irunlarrea 1, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research, IdiSNA, Irunlarrea 3, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0359-3959","authenticated-orcid":false,"given":"Lucie","family":"Paloque","sequence":"additional","affiliation":[{"name":"LCC-CNRS, Universit\u00e9 de Toulouse, CNRS UPR8241, UPS, 31400 Toulouse, France"},{"name":"MAAP, New Antimalarial Molecules and Pharmacological Approaches, MAAP, Inserm ERL 1289, 31400 Toulouse, France"},{"name":"Institut de Pharmacologie et de Biologie Structurale, IPBS, Universit\u00e9 de Toulouse, CNRS, UPS, 31400 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Cohen","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, IHU M\u00e9diterran\u00e9e Infection, UMR VITROME, IRD, SSA, Mycology & Tropical Eucaryotic Pathogens, CEDEX 05, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6758-5803","authenticated-orcid":false,"given":"Nadia","family":"Amanzougaghene","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, CNRS, Centre d\u2019Immunologie et des Maladies Infectieuses, CIMI, 75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahin","family":"Tajeri","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, CNRS, Centre d\u2019Immunologie et des Maladies Infectieuses, CIMI, 75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Fran\u00e7ois","family":"Franetich","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, CNRS, Centre d\u2019Immunologie et des Maladies Infectieuses, CIMI, 75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8059-1810","authenticated-orcid":false,"given":"Dominique","family":"Mazier","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, CNRS, Centre d\u2019Immunologie et des Maladies Infectieuses, CIMI, 75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9468-4823","authenticated-orcid":false,"given":"Fran\u00e7oise","family":"Benoit-Vical","sequence":"additional","affiliation":[{"name":"LCC-CNRS, Universit\u00e9 de Toulouse, CNRS UPR8241, UPS, 31400 Toulouse, France"},{"name":"MAAP, New Antimalarial Molecules and Pharmacological Approaches, MAAP, Inserm ERL 1289, 31400 Toulouse, France"},{"name":"Institut de Pharmacologie et de Biologie Structurale, IPBS, Universit\u00e9 de Toulouse, CNRS, UPS, 31400 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Verhaeghe","sequence":"additional","affiliation":[{"name":"LCC-CNRS, Universit\u00e9 de Toulouse, CNRS UPR8241, UPS, 31400 Toulouse, France"},{"name":"CHU de Toulouse, Service Pharmacie, 330 Avenue de Grande-Bretagne, CEDEX 9, 31059 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9075-8303","authenticated-orcid":false,"given":"Nadine","family":"Azas","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, IHU M\u00e9diterran\u00e9e Infection, UMR VITROME, IRD, SSA, Mycology & Tropical Eucaryotic Pathogens, CEDEX 05, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrice","family":"Vanelle","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Facult\u00e9 de Pharmacie, CEDEX 05, 13385 Marseille, France"},{"name":"APHM, H\u00f4pital Conception, Service Central de la Qualit\u00e9 et de l\u2019Information Pharmaceutiques, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrille","family":"Bott\u00e9","sequence":"additional","affiliation":[{"name":"ApicoLipid Team, Institute for Advanced Biosciences, 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