{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:31:52Z","timestamp":1790703112257,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,6,18]],"date-time":"2020-06-18T00:00:00Z","timestamp":1592438400000},"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":["INMAR ANR16 CE35 0003"],"award-info":[{"award-number":["INMAR ANR16 CE35 0003"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The emergence of Plasmodium falciparum parasites, responsible for malaria disease, resistant to antiplasmodial drugs including the artemisinins, represents a major threat to public health. Therefore, the development of new antimalarial drugs or combinations is urgently required. In this context, several hybrid molecules combining a dihydroartemisinin derivative and gold(I) N-heterocyclic carbene (NHC) complexes have been synthesized based on the different modes of action of the two compounds. The antiplasmodial activity of these molecules was assessed in vitro as well as their cytotoxicity against mammalian cells. All the hybrid molecules tested showed efficacy against P. falciparum, in a nanomolar range for the most active, associated with a low cytotoxicity. However, cross-resistance between artemisinin and these hybrid molecules was evidenced. These results underline a fear about the risk of cross-resistance between artemisinins and new antimalarial drugs based on an endoperoxide part. This study thus raises concerns about the use of such molecules in future therapeutic malaria policies.<\/jats:p>","DOI":"10.3390\/molecules25122817","type":"journal-article","created":{"date-parts":[[2020,6,18]],"date-time":"2020-06-18T12:21:46Z","timestamp":1592482906000},"page":"2817","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Hybrid Gold(I) NHC-Artemether Complexes to Target Falciparum Malaria Parasites"],"prefix":"10.3390","volume":"25","author":[{"given":"Manel","family":"Ouji","sequence":"first","affiliation":[{"name":"CNRS, Laboratoire de Chimie de Coordination (LCC), Universit\u00e9 de Toulouse, UPS, INPT, 205 route de Narbonne, BP 44099, F-31077 Toulouse CEDEX 4, France"},{"name":"Institut de Pharmacologie et de Biologie Structurale, IPBS, Universit\u00e9 de Toulouse, CNRS, UPS, 31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Barnoin","sequence":"additional","affiliation":[{"name":"CNRS, Laboratoire de Chimie de Coordination (LCC), Universit\u00e9 de Toulouse, UPS, INPT, 205 route de Narbonne, BP 44099, F-31077 Toulouse CEDEX 4, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1lvaro","family":"Fern\u00e1ndez \u00c1lvarez","sequence":"additional","affiliation":[{"name":"CNRS, Laboratoire de Chimie de Coordination (LCC), Universit\u00e9 de Toulouse, UPS, INPT, 205 route de Narbonne, BP 44099, F-31077 Toulouse CEDEX 4, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Augereau","sequence":"additional","affiliation":[{"name":"CNRS, Laboratoire de Chimie de Coordination (LCC), Universit\u00e9 de Toulouse, UPS, INPT, 205 route de Narbonne, BP 44099, F-31077 Toulouse CEDEX 4, France"},{"name":"Institut de Pharmacologie et de Biologie Structurale, IPBS, Universit\u00e9 de Toulouse, CNRS, UPS, 31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Hemmert","sequence":"additional","affiliation":[{"name":"CNRS, Laboratoire de Chimie de Coordination (LCC), Universit\u00e9 de Toulouse, UPS, INPT, 205 route de Narbonne, BP 44099, F-31077 Toulouse CEDEX 4, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Benoit-Vical","sequence":"additional","affiliation":[{"name":"CNRS, Laboratoire de Chimie de Coordination (LCC), Universit\u00e9 de Toulouse, UPS, INPT, 205 route de Narbonne, BP 44099, F-31077 Toulouse CEDEX 4, France"},{"name":"Institut de Pharmacologie et de Biologie Structurale, IPBS, Universit\u00e9 de Toulouse, CNRS, UPS, 31077 Toulouse, France"},{"name":"INSERM, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, 31024 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinz","family":"Gornitzka","sequence":"additional","affiliation":[{"name":"CNRS, Laboratoire de Chimie de Coordination (LCC), Universit\u00e9 de Toulouse, UPS, INPT, 205 route de Narbonne, BP 44099, F-31077 Toulouse CEDEX 4, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,18]]},"reference":[{"key":"ref_1","unstructured":"World Health Organisation (2018). World Malaria Report, WHO."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"716","DOI":"10.3201\/eid1405.071601","article-title":"Declining Artesunate-Mefloquine Efficacy against Falciparum Malaria on the Cambodia\u2013Thailand Border","volume":"14","author":"Wongsrichanalai","year":"2008","journal-title":"Emerg. Infect. Dis. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/S1473-3099(16)30409-1","article-title":"Genetic markers associated with dihydroartemisinin\u2013piperaquine failure in Plasmodium falciparum malaria in Cambodia: A genotype\u2013phenotype association study","volume":"17","author":"Amato","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/S1473-3099(16)30415-7","article-title":"A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: A phenotype\u2013genotype association study","volume":"17","author":"Witkowski","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1051\/parasite\/2018021","article-title":"Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination","volume":"25","author":"Ouji","year":"2018","journal-title":"Parasite"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3599","DOI":"10.1016\/j.bmcl.2007.04.054","article-title":"A novel artemisinin-quinine hybrid with potent antimalarial activity","volume":"17","author":"Walsh","year":"2007","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_7","first-page":"7360","article-title":"Artemisinin-derived dimers: Potent antimalarial and anticancer agents","volume":"59","author":"Reiter","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3","DOI":"10.4103\/wjtcm.wjtcm_10_17","article-title":"New orally active artemisinin dimer antimalarials","volume":"3","author":"Elsohly","year":"2017","journal-title":"World J. Tradit. Chin. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1128\/AAC.01636-09","article-title":"Increased tolerance to artemisinin in plasmodium falciparum is mediated by a quiescence mechanism","volume":"54","author":"Witkowski","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature12876","article-title":"A molecular marker of artemisinin-resistant Plasmodium falciparum malaria","volume":"505","author":"Ariey","year":"2014","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1086\/656476","article-title":"Artemisinin-Induced Dormancy in Plasmodium falciparum: Duration, Recovery Rates, and Implications in Treatment Failure","volume":"202","author":"Teuscher","year":"2010","journal-title":"J. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1093\/infdis\/jiy673","article-title":"Artemisinin Resistance and Stage Dependency of Parasite Clearance in Falciparum Malaria","volume":"219","author":"Intharabut","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1186\/s12936-016-1206-9","article-title":"Plasmodium falciparum: Multifaceted resistance to artemisinins","volume":"15","author":"Paloque","year":"2016","journal-title":"Malar. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4773","DOI":"10.1128\/AAC.02647-14","article-title":"Fatty acid synthesis and pyruvate metabolism pathways remain active in dihydroartemisinin-induced dormant ring stages of plasmodium falciparum","volume":"58","author":"Chen","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.3201\/eid2110.150682","article-title":"Induction of multidrug tolerance in Plasmodium falciparum by extended artemisinin pressure","volume":"21","author":"Haddou","year":"2015","journal-title":"Emerg. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1093\/infdis\/jiv048","article-title":"Mitochondrial Membrane Potential in a Small Subset of Artemisinin-Induced Dormant Plasmodium falciparum Parasites in vitro","volume":"212","author":"Peatey","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"25970","DOI":"10.1074\/jbc.M203539200","article-title":"Thioredoxin reductase is essential for the survival of Plasmodium falciparum erythrocytic stages","volume":"277","author":"Krnajski","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ejmech.2012.11.038","article-title":"Synthesis, structures, and antimalarial activities of some silver(I), gold(I) and gold(III) complexes involving N-heterocyclic carbene ligands","volume":"60","author":"Hemmert","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.1016\/j.bmc.2016.05.023","article-title":"Antiplasmodial activities of gold(I) complexes involving functionalized N-heterocyclic carbenes","volume":"24","author":"Hemmert","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1002\/slct.201904345","article-title":"Design, Synthesis and Efficacy of Hybrid Triclosan-gold Based Molecules on Artemisinin-resistant Plasmodium falciparum and Leishmania infantum Parasites","volume":"5","author":"Ouji","year":"2020","journal-title":"ChemistrySelect"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.ejmech.2015.02.046","article-title":"Synthesis, characterization, and antileishmanial activities of gold(I) complexes involving quinoline functionalized N-heterocyclic carbenes","volume":"94","author":"Paloque","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1016\/j.ejmech.2017.10.060","article-title":"Synthesis, characterization, and antileishmanial activity of neutral N-heterocyclic carbenes gold(I) complexes","volume":"143","author":"Zhang","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.ejmech.2014.07.086","article-title":"Synthesis, structures, and selective toxicity to cancer cells of gold(I) complexes involving N-heterocyclic carbene ligands","volume":"85","author":"Boselli","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1002\/cmdc.201800181","article-title":"Cationic and Neutral N-Heterocyclic Carbene Gold(I) Complexes: Cytotoxicity, NCI-60 Screening, Cellular Uptake, Inhibition of Mammalian Thioredoxin Reductase, and Reactive Oxygen Species Formation","volume":"13","author":"Zhang","year":"2018","journal-title":"ChemMedChem"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.ejmech.2018.07.070","article-title":"Pharmacomodulation on Gold-NHC complexes for anticancer applications\u2014Is lipophilicity the key point?","volume":"157","author":"Zhang","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1016\/j.ccr.2009.02.026","article-title":"Thioredoxin reductase: A target for gold compounds acting as potential anticancer drugs","volume":"253","author":"Bindoli","year":"2009","journal-title":"Coord. Chem. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1002\/cbic.200400366","article-title":"Convenient Access Both to Highly Antimalaria-Active 10-Arylaminoartemisinins, and to 10-Alkyl Ethers Including Artemether, Arteether, and Artelinate","volume":"6","author":"Haynes","year":"2005","journal-title":"ChemBioChem"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zhang, C., Fortin, P.-Y., Barnoin, G., Qin, X., Wang, X., Fernandez Alvarez, A., Bijani, C., Maddelein, M.-L., Hemmert, C., and Cuvillier, O. (2020). Artemisinin-Derivative-NHC-gold(I)-Hybrid with Enhanced Cytotoxic Activity Through Inhibiting NRF2 Transcriptional Activity. Angew. Chem. Int. Ed.","DOI":"10.26434\/chemrxiv.11629113"},{"key":"ref_29","unstructured":"Strassner, T., Unger, Y., and Zeller, A. (2009). Use of Pt- and Pd-bis- and tetracarbon complexes with bridged carbon ligands in OLEDs. (20090326237)."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1128\/AAC.01868-12","article-title":"Reduced artemisinin susceptibility of Plasmodium falciparum ring stages in western Cambodia","volume":"57","author":"Witkowski","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1093\/jac\/dkx412","article-title":"Endoperoxide-based compounds: Cross-resistance with artemisinins and selection of a Plasmodium falciparum lineage with a K13 non-synonymous polymorphism","volume":"73","author":"Paloque","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e00172-17","DOI":"10.1128\/mBio.00172-17","article-title":"Plasmodium falciparum K13 mutations differentially impact ozonide susceptibility and parasite fitness in vitro","volume":"8","author":"Straimer","year":"2017","journal-title":"MBio"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1128\/AAC.16.6.710","article-title":"Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique","volume":"16","author":"Desjardins","year":"1979","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"418","DOI":"10.2307\/3280287","article-title":"Synchronization of Plasmodium falciparum Erythrocytic Stages in Culture","volume":"65","author":"Lambros","year":"1979","journal-title":"J. Parasitol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0304-3835(98)00222-5","article-title":"Antitumor activity of triptolide against cholangiocarcinoma growth in vitro and in hamsters","volume":"133","author":"Tengchaisri","year":"1998","journal-title":"Cancer Lett."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/12\/2817\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:40:28Z","timestamp":1760175628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/12\/2817"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,18]]},"references-count":35,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["molecules25122817"],"URL":"https:\/\/doi.org\/10.3390\/molecules25122817","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,18]]}}}