Synthesis and evaluation of (Bis)benzyltetrahydroisoquinoline alkaloids as antiparasitic agents
JACS Au, v. 7, n. 2, p. 847-854, fev. 2024
Artigo
em Inglês
| Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP
| ID: bud-5293
Biblioteca responsável:
BR78.1
ABSTRACT
Visceral leishmaniasis and Chagas disease are neglected tropical diseases (NTDs) that severely impact the developing world. With current therapies suffering from poor efficacy and safety profiles as well as emerging resistance, new drug leads are direly needed. In this work, 26 alkaloids (9 natural and 17 synthetic) belonging to the benzyltetrahydroisoquinoline (BI) family were evaluated against both the pro/trypomastigote and amastigote forms of the parasites Leishmania infantum and Trypanosoma cruzi, the causative agents of these diseases. These alkaloids were synthesized via an efficient and modular enantioselective approach based on Bischler-Napieralski cyclization/Noyori asymmetric transfer hydrogenation to build the tetrahydroisoquinoline core. The bis-benzyltetrahydroisoquinoline (BBI) alkaloids were prepared using an Ullmann coupling of two BI units to form the biaryl ether linkage, which enabled a comprehensive survey of the influence of BI stereochemistry on bioactivity. Preliminary studies into the mechanism of action against Leishmania mexicana demonstrate that these compounds interfere with the cell cycle, potentially through inhibition of kinetoplast division, which may offer opportunities to identify a new target/mechanism of action. Three of the synthesized alkaloids showed promising druglike potential, meeting the Drugs for Neglected Disease initiative (DNDi) criteria for a hit against Chagas disease.
Texto completo:
Disponível
Coleções:
Bases de dados nacionais
/
Brasil
Contexto em Saúde:
ODS3 - Saúde e Bem-Estar
/
Doenças Negligenciadas
/
ODS3 - Meta 3.3 Acabar com as doenças tropicais negligenciadas e combater as doenças transmissíveis
Problema de saúde:
Meta 3.3: Acabar com as doenças tropicais negligenciadas e combater as doenças transmissíveis
/
Doença de Chagas
/
Doenças Negligenciadas
/
AIDS
Base de dados:
Sec. Est. Saúde SP
/
SESSP-IBPROD
Idioma:
Inglês
Revista:
JACS Au
Ano de publicação:
2024
Tipo de documento:
Artigo