{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:03:42Z","timestamp":1790730222085,"version":"4.1.0"},"reference-count":24,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T00:00:00Z","timestamp":1748908800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CNRS innovation","award":["ANR-22-CE93-0005-01"],"award-info":[{"award-number":["ANR-22-CE93-0005-01"]}]},{"name":"CNRS innovation","award":["ANR-17-CE15-0013-01"],"award-info":[{"award-number":["ANR-17-CE15-0013-01"]}]},{"name":"CNRS innovation","award":["ANR-11-LABX-0024"],"award-info":[{"award-number":["ANR-11-LABX-0024"]}]},{"name":"CNRS innovation","award":["ANR-MRSEI 2018"],"award-info":[{"award-number":["ANR-MRSEI 2018"]}]},{"name":"Agence Nationale de la Recherche (ANR) and the (FNS)","award":["ANR-22-CE93-0005-01"],"award-info":[{"award-number":["ANR-22-CE93-0005-01"]}]},{"name":"Agence Nationale de la Recherche (ANR) and the (FNS)","award":["ANR-17-CE15-0013-01"],"award-info":[{"award-number":["ANR-17-CE15-0013-01"]}]},{"name":"Agence Nationale de la Recherche (ANR) and the (FNS)","award":["ANR-11-LABX-0024"],"award-info":[{"award-number":["ANR-11-LABX-0024"]}]},{"name":"Agence Nationale de la Recherche (ANR) and the (FNS)","award":["ANR-MRSEI 2018"],"award-info":[{"award-number":["ANR-MRSEI 2018"]}]},{"name":"European Campus EUCOR","award":["ANR-22-CE93-0005-01"],"award-info":[{"award-number":["ANR-22-CE93-0005-01"]}]},{"name":"European Campus EUCOR","award":["ANR-17-CE15-0013-01"],"award-info":[{"award-number":["ANR-17-CE15-0013-01"]}]},{"name":"European Campus EUCOR","award":["ANR-11-LABX-0024"],"award-info":[{"award-number":["ANR-11-LABX-0024"]}]},{"name":"European Campus EUCOR","award":["ANR-MRSEI 2018"],"award-info":[{"award-number":["ANR-MRSEI 2018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Plasmodione is a potent early antiplasmodial compound. A metabolic study on mice treated with plasmodione revealed that 6-hydroxy\u2013plasmodione was the main metabolite eliminated in the urine of treated mice. To block the metabolic pathway in the host, the introduction of fluorine at C-6 of the 3-benzylmenadione core was applied and showed potent antiplasmodial activity similar to that of the plasmodione analogue in vitro. In this work, a library of 38 6-fluoro-3-benzylmenadione analogues (a series) was constructed by incorporating structurally diverse groups in place of the 4-(trifluoromethyl) substituent present in the antiplasmodial plasmodione, via three synthetic routes. All new compounds were tested against the P. falciparum NF54 strain and for cytotoxicity with the rat L6 line. With a fluorine atom at C-6, A-a-21 was revealed to be the only compound from the a series, superior to the 6-H- analogue from the b series, with an IC50 value of 70 nM versus 200 nM. Then, five other fluorine-based 3-benzylmenadiones, in which the fluorine was introduced in various positions of the 3-benzylmenadione core, were synthetized to assist our understanding of the impact of fluorine on antiplasmodial potencies in vitro; in particular, the aim here was to compare the effects of human serum and P. berghei species in these drug screens. This was also conducted in vivo with the P. berghei-infected mouse model. In the P. berghei species assay, PD and the 4\u2032-fluoro-3\u2032-trifluoromethyl-benzylmenadione A-b-9 exhibited a similar antiplasmodial behavior toward P. falciparum versus P. berghei. In the human serum versus Albumax assays, only the 6-fluoro\u2013plasmodione showed a lower shift factor between Albumax assays and human serum conditions, suggesting a lower protein binding for the 6-F-PD compared to plasmodione or A-b-9. In vivo, 6-fluoro\u2013plasmodione proved to be the most potent 3-benzylmenadione, reducing parasitemia by 50% after oral administration at 50 mg\/kg.<\/jats:p>","DOI":"10.3390\/molecules30112446","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T06:21:51Z","timestamp":1748931711000},"page":"2446","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Design, Synthesis and Antiplasmodial Activities of a Library of Fluorine-Based 3-Benzylmenadiones"],"prefix":"10.3390","volume":"30","author":[{"given":"Matthieu","family":"Roignant","sequence":"first","affiliation":[{"name":"Laboratoire d\u2019Innovation Mol\u00e9culaire et Applications (LIMA), Team Bio(IN)organic and Medicinal Chemistry, European School of Chemistry, Polymers and Materials (ECPM), UMR7042 Universit\u00e9 de Strasbourg-CNRS-UHA, 25 rue Becquerel, F-67087 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy","family":"Richard","sequence":"additional","affiliation":[{"name":"Laboratoire d\u2019Innovation Mol\u00e9culaire et Applications (LIMA), Team Bio(IN)organic and Medicinal Chemistry, European School of Chemistry, Polymers and Materials (ECPM), UMR7042 Universit\u00e9 de Strasbourg-CNRS-UHA, 25 rue Becquerel, F-67087 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxime","family":"Donzel","sequence":"additional","affiliation":[{"name":"Laboratoire d\u2019Innovation Mol\u00e9culaire et Applications (LIMA), Team Bio(IN)organic and Medicinal Chemistry, European School of Chemistry, Polymers and Materials (ECPM), UMR7042 Universit\u00e9 de Strasbourg-CNRS-UHA, 25 rue Becquerel, F-67087 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2207-7899","authenticated-orcid":false,"given":"Matthias","family":"Rottmann","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute, Kreuzstrasse 2, CH-4123 Allschwil, Switzerland"},{"name":"University of Basel, Petersgraben 1, CH-4001 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3122-1941","authenticated-orcid":false,"given":"Pascal","family":"M\u00e4ser","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute, Kreuzstrasse 2, CH-4123 Allschwil, Switzerland"},{"name":"University of Basel, Petersgraben 1, CH-4001 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7026-4034","authenticated-orcid":false,"given":"Elisabeth","family":"Davioud-Charvet","sequence":"additional","affiliation":[{"name":"Laboratoire d\u2019Innovation Mol\u00e9culaire et Applications (LIMA), Team Bio(IN)organic and Medicinal Chemistry, European School of Chemistry, Polymers and Materials (ECPM), UMR7042 Universit\u00e9 de Strasbourg-CNRS-UHA, 25 rue Becquerel, F-67087 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,3]]},"reference":[{"key":"ref_1","unstructured":"WHO (2023). World Malaria Report 2023, WHO. Global Report."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"E591","DOI":"10.1016\/S1473-3099(24)00141-5","article-title":"The emergence of artemisinin partial resistance in Africa: How do we respond?","volume":"24","author":"Rosenthal","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1002\/cmdc.200600156","article-title":"Fluoroartemisinins: Metabolically more stable antimalarial artemisinin derivatives","volume":"2","year":"2007","journal-title":"ChemMedChem"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1039\/B610213C","article-title":"Fluorine in medicinal chemistry","volume":"37","author":"Purser","year":"2008","journal-title":"Chem. Soc. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5146","DOI":"10.1128\/AAC.02975-15","article-title":"The redox-cycler plasmodione is a fast-acting antimalarial lead compound with pronounced activity against sexual and early asexual blood-stage parasites","volume":"60","author":"Ehrhardt","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1089\/ars.2014.6047","article-title":"Antimalarial NADPH-consuming redox-cyclers as superior G6PD deficiency copycats","volume":"22","author":"Bielitza","year":"2015","journal-title":"Antioxid. Redox Signal."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.1039\/C8OB00227D","article-title":"Synthesis of plasmodione metabolites and 13C-enriched plasmodione as chemical tools for drug metabolism investigation","volume":"16","author":"Feng","year":"2018","journal-title":"Org. Biomol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11557","DOI":"10.1021\/ja201729z","article-title":"Glutathione Reductase-Catalyzed Cascade of Redox Reactions to Bioactivate Potent Antimalarial 1,4-Naphthoquinones\u2014A New Strategy to Combat Malarial Parasites","volume":"133","author":"Johann","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10055","DOI":"10.1021\/acs.joc.1c00814","article-title":"Bioinspired Photoredox Benzylation of Quinones","volume":"86","author":"Donzel","year":"2021","journal-title":"J. Org. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3553","DOI":"10.1021\/acsinfecdis.4c00304","article-title":"3-Benzylmenadiones and their heteroaromatic analogues target the apicoplast of Apicomplexa parasites: Synthesis and bioimaging studies","volume":"10","author":"Dupouy","year":"2024","journal-title":"ACS Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1021\/acs.oprd.1c00421","article-title":"Efficient Multigram-Scale Synthesis of 7-Substituted 3-Methylteral-1-ones and 6-Fluoromenadione","volume":"26","author":"Trometer","year":"2022","journal-title":"Org. Process Res. Dev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1002\/ejoc.201600144","article-title":"A Platform of Regioselective Methodologies to Access Polysubstituted 2-Methyl-1,4-naphthoquinone Derivatives: Scope and Limitations","volume":"2016","author":"Rodo","year":"2016","journal-title":"Eur. J. Org. Chem."},{"key":"ref_13","unstructured":"Davioud-Charvet, E., M\u00fcller, T., Bauer, H., and Schirmer, H. (2009). 1,4-Naphthoquinone Derivatives, Their Preparation, Pharmaceutical Compositions, and Use as Antimalarial Agents. (WO2009118327 A1)."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1246\/cl.190138","article-title":"Acid-induced Control of Surface Properties Using a Catecholic Silane Coupling Reagent","volume":"48","author":"Kohri","year":"2019","journal-title":"Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"13298","DOI":"10.1021\/acs.joc.0c01729","article-title":"Fluorodesulfurization of Thionobenzodioxoles with Silver(I) Fluoride","volume":"85","author":"Newton","year":"2020","journal-title":"J. Org. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4824","DOI":"10.1002\/ejoc.200800544","article-title":"One-Pot Dual Substitutions of Bromobenzyl Chloride, 2-Chloromethyl-6-halogenoimidazo[1,2-a]pyridine and -[1,2-b]pyridazine by Suzuki\u2013Miyaura Cross-Coupling Reactions","volume":"2008","author":"Henry","year":"2008","journal-title":"Eur. J. Org. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1126\/science.781840","article-title":"Human malaria parasites in continuous culture","volume":"193","author":"Trager","year":"1976","journal-title":"Science"},{"key":"ref_18","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_19","doi-asserted-by":"crossref","unstructured":"Presser, A., Blaser, G., Pferschy-Wenzig, E.M., Kaiser, M., M\u00e4ser, P., and Schuehly, W. (2025). Pharmacomodulation of the Redox-Active Lead Plasmodione: Synthesis of Substituted 2-Benzylnaphthoquinone Derivatives, Antiplasmodial Activities, and Physicochemical Properties. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26052114"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1002\/cmdc.201600298","article-title":"Discovery and Characterization of ACT-451840: An Antimalarial Drug with a Novel Mechanism of Action","volume":"11","author":"Boss","year":"2016","journal-title":"ChemMedChem"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Cesar-Rodo, E., Dupouy, B., H\u00e4berli, C., Williams, D.L., Strub, J.-M., M\u00e4ser, P., Rottmann, M., Keiser, J., Lanfranchi, D.A., and Davioud-Charvet, E. (2024). Regioselective synthesis of potential non-quinonoid prodrugs of plasmodione: Drug metabolism studies and antiparasitic properties against two hemoglobin-feeding parasites. Molecules, 29.","DOI":"10.3390\/molecules29225268"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1038\/nature02779","article-title":"Identification of an antimalarial synthetic trioxolane drug development candidate","volume":"430","author":"Vennerstrom","year":"2004","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1128\/AAC.41.3.677","article-title":"Antimalarial activity of the bisquinoline trans-N1,N2-bis-(7-chloroquinolin-4-yl)cyclohexane-1,2-diamine: Comparison of two stereoisomers and detailed evaluation of the S,S enantiomer, Ro 47-7737","volume":"41","author":"Ridley","year":"1997","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_24","unstructured":"Peters, W. (1987). Chemotherapy and Drug Resistance in Malaria, Academic Press."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/11\/2446\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:46:33Z","timestamp":1760031993000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/11\/2446"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,3]]},"references-count":24,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["molecules30112446"],"URL":"https:\/\/doi.org\/10.3390\/molecules30112446","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,3]]}}}