Buchwald reaction as the key step for the synthesis of metabolically more stable analogs of amodiaquine

Amodiaquine is one of the most active anti-malarial 4-aminoquinoline but its metabolization is believed to generate hepatotoxic derivatives. Previously, we described new analogs of amodiaquine and amopyroquine, in which hydroxyl group was replaced by various amino groups and identified highly potent compounds with lower toxicity. We describe here the synthesis of new analogs that have been modified on their 4′- and 5′-positions in order to reduce their metabolization. A new synthetic strategy was developed using Buchwald coupling reaction as the key step.

Graphical abstractThe synthesis of new amodiaquine analogs modified on 4′- and 5′-positions was developed using Buchwald cross-coupling reaction as the key step.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 4-Aminoquinolineanalogs of amodiaquine. ► Compounds designed to avoid metabolization issues leading to hepatotoxicity. ► Original and very efficient synthesis using Buchwald and Tcherniak-Einhorn reactions.