Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3-Benzylmenadione Revealed by High-Content Imaging.
Fiche publication
Date publication
avril 2024
Journal
ACS infectious diseases
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DAVIOUD-CHARVET Elisabeth
Tous les auteurs :
Trometer N, Pecourneau J, Feng L, Navarro-Huerta JA, Lazarin-Bidóia D, de Oliveira Silva Lautenschlager S, Maes L, Fortes Francisco A, Kelly JM, Meunier B, Cal M, Mäser P, Kaiser M, Davioud-Charvet E
Lien Pubmed
Résumé
Chagas disease, or American trypanosomiasis, is a neglected tropical disease which is a top priority target of the World Health Organization. The disease, endemic mainly in Latin America, is caused by the protozoan and has spread around the globe due to human migration. There are multiple transmission routes, including vectorial, congenital, oral, and iatrogenic. Less than 1% of patients have access to treatment, relying on two old redox-active drugs that show poor pharmacokinetics and severe adverse effects. Hence, the priorities for the next steps of R&D include (i) the discovery of novel drugs/chemical classes, (ii) filling the pipeline with drug candidates that have new mechanisms of action, and (iii) the pressing need for more research and access to new chemical entities. In the present work, we first identified a hit () with a potent anti- activity from a library of 3-benzylmenadiones. We then designed a synthetic strategy to build a library of 49 3-(4-monoamino)benzylmenadione derivatives via reductive amination to obtain diazacyclic benz(o)ylmenadiones. Among them, we identified by high content imaging an anti-amastigote "early lead" (henceforth called cruzidione) revealing optimized pharmacokinetic properties and enhanced specificity. Studies in a yeast model revealed that a cruzidione metabolite, the 3-benzoylmenadione (cruzidione oxide), enters redox cycling with the NADH-dehydrogenase, generating reactive oxygen species, as hypothesized for the early hit ().
Mots clés
3-benzylmenadione, Chagas disease, Trypanosoma cruzi, oxidative stress, redox, yeast NADH-dehydrogenase
Référence
ACS Infect Dis. 2024 04 12;: