Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3‑Benzylmenadione Revealed by High-Content Imaging

• Published in: ACS infectious diseases Vol. 10; no. 5; pp. 1808 - 1838
• Main Authors: Trometer, Nathan, Pecourneau, Jérémy, Feng, Liwen, Navarro-Huerta, José A., Lazarin-Bidóia, Danielle, de Oliveira Silva Lautenschlager, Sueli, Maes, Louis, Fortes Francisco, Amanda, Kelly, John M., Meunier, Brigitte, Cal, Monica, Mäser, Pascal, Kaiser, Marcel, Davioud-Charvet, Elisabeth
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10-05-2024
• Subjects: Animals; Chagas Disease - drug therapy; Humans; Mice; Oxidation-Reduction; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma cruzi - drug effects; Chagas disease; yeast NADH-dehydrogenase; 3-benzylmenadione; oxidative stress; redox; Trypanosoma cruzi
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.4c00137

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 Trypanosoma cruzi 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 (4a) with a potent anti-T. cruzi 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” 11b (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 (4a).