Facile Access to Structurally Diverse Antimalarial Indoles Using a One-Pot A(3) Coupling and Domino Cyclization Approach

A multistep and diversity-oriented synthetic route aiming at the A(3) coupling/domino cyclization of o-ethynyl anilines, aldehydes and s-amines is described. The preparation of the corresponding precursors included a series of transformations, such as haloperoxidation and Sonogashira cross-coupling reactions, amine protection, desilylation and amine reduction. Some products of the multicomponent reaction underwent further detosylation and Suzuki coupling. The resulting library of structurally diverse compounds was evaluated against blood and liver stage malaria parasites, which revealed a promising lead with sub-micromolar activity against intra-erythrocytic forms of Plasmodium falciparum. The results from this hit-to-lead optimization are hereby reported for the first time.

Automated summary

This study presents a multistep and diversity-oriented synthetic route for the A(3) coupling/domino cyclization of o-ethynyl anilines, aldehydes, and s-amines. The preparation of precursors involved various transformations, including haloperoxidation, Sonogashira cross-coupling reactions, amine protection, desilylation, and amine reduction. Some products underwent detosylation and Suzuki coupling. The resulting library of diverse compounds showed promising activity against Plasmodium falciparum's intra-erythrocytic forms, providing valuable hit-to-lead optimization results.