Author(s):
da Silva, Gustavo ; Luz, André F.S. ; Duarte, Denise ; Fontinha, Diana ; Silva, Vera L.M. ; Almeida Paz, Filipe A. ; Madureira, Ana M. ; Simões, Sandra ; Prudêncio, Miguel ; Nogueira, Fátima ; Silva, Artur M.S. ; Moreira, Rui
Date: 2023
Persistent ID: http://hdl.handle.net/10362/158923
Origin: Repositório Institucional da UNL
Subject(s): A coupling; antimalarials; indoles; multicomponent reactions; one-pot synthesis; Biochemistry; Molecular Medicine; Pharmacology; Drug Discovery; Pharmacology, Toxicology and Pharmaceutics(all); Organic Chemistry; Parasitology; SDG 3 - Good Health and Well-being
Description
Funding Information: . The authors acknowledge the financial support provided by Fundação para a Ciência e a Tecnologia (FCT Portugal) through the PhD grant research project SFRH/BD/103412/2014 and projects PTDC/MED‐QUI/30021/2017, PTDC/MED‐CAR/31322/2017 and PTDC/SAU‐TOX/32515/2017, and the research unit GHTM (UID/Multi/04413/2013 and GHTM‐UID/04413/2020). We thank MR4 for providing us with malaria parasites contributed by Andrew Talman, Robert Sinden Funding Information: The authors acknowledge the financial support provided by Fundação para a Ciência e a Tecnologia (FCT Portugal) through the PhD grant research project SFRH/BD/103412/2014 and projects PTDC/MED-QUI/30021/2017, PTDC/MED-CAR/31322/2017 and PTDC/SAU-TOX/32515/2017, and the research unit GHTM (UID/Multi/04413/2013 and GHTM-UID/04413/2020). We thank MR4 for providing us with malaria parasites contributed by Andrew Talman, Robert Sinden. Publisher Copyright: © 2023 Wiley-VCH GmbH.
A multistep and diversity-oriented synthetic route aiming at the A3 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.
