resumo
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.
palavras-chave
ARTEMISININ RESISTANCE; MOLECULAR-MECHANISM; IN-VITRO; SCAFFOLD
categoria
Pharmacology & Pharmacy
autores
da Silva, G; Luz, AFS; Duarte, D; Fontinha, D; Silva, VLM; Paz, FAA; Madureira, AM; Simos, S; Prudêncio, M; Nogueira, F; Silva, AMS; Moreira, R
nossos autores
Filipe Alexandre Almeida Paz
Investigador Principalagradecimentos
The authors acknowledge the financial support provided by Fundacao para a Ciencia 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.