Design, Synthesis and Antiplasmodial Activities of a Library of Fluorine-Based 3-Benzylmenadiones.

Fiche publication

Date publication

juin 2025

Journal

Molecules (Basel, Switzerland)

Auteurs

Membres identifiés du Cancéropôle Est :
Dr DAVIOUD-CHARVET Elisabeth

Tous les auteurs :
Roignant M, Richard J, Donzel M, Rottmann M, Mäser P, Davioud-Charvet E

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/40509333

Résumé

Plasmodione is a potent early antiplasmodial compound. A metabolic study on mice treated with plasmodione revealed that 6-hydroxy-plasmodione 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 ( 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 NF54 strain and for cytotoxicity with the rat L6 line. With a fluorine atom at C-6, was revealed to be the only compound from the series, superior to the 6-H- analogue from the series, with an IC 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 species in these drug screens. This was also conducted in vivo with the -infected mouse model. In the species assay, PD and the 4'-fluoro-3'-trifluoromethyl-benzylmenadione exhibited a similar antiplasmodial behavior toward versus In the human serum versus Albumax assays, only the 6-fluoro-plasmodione 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 . In vivo, 6-fluoro-plasmodione proved to be the most potent 3-benzylmenadione, reducing parasitemia by 50% after oral administration at 50 mg/kg.