A semi-synthetic neolignan derivative from dihydrodieugenol B selectively affects the bioenergetic system of Leishmania infantum and inhibits cell division

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art_AMARAL_A_semisynthetic_neolignan_derivative_from_dihydrodieugenol_B_selectively_2019.PDF (2.03 MB)
Citações na Scopus
24
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article
Data de publicação
2019
Editora
NATURE PUBLISHING GROUP
DOI
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Scopus
Web of Science
PubMed
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Autores
AMARAL, Maiara
SOUSA, Fernanda S. de
SILVA, Thais A. Costa
TANIWAKI, Noemi N.
JOHNS, Deid Re M.
LAGO, Joao Henrique G.
ANDERSON, Edward A.
TEMPONE, Andre G.
Autor de Grupo de pesquisa
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Citação
SCIENTIFIC REPORTS, v.9, article ID 6114, 15p, 2019
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Leishmaniasis is a neglected disease that affects more than 12 million people, with a limited therapy. Plant-derived natural products represent a useful source of anti-protozoan prototypes. In this work, four derivatives were prepared from neolignans isolated from the Brazilian plant Nectandra leucantha, and their effects against intracellular amastigotes of Leishmania (L.) infantum evaluated in vitro. IC50 values between 6 and 35 mu M were observed and in silico predictions suggested good oral bioavailability, no PAINS similarities, and ADMET risks typical of lipophilic compounds. The most selective (SI > 32) compound was chosen for lethal action and immunomodulatory studies. This compound caused a transient depolarization of the plasma membrane potential and induced an imbalance of intracellular Ca2+, possibly resulting in a mitochondrial impairment and leading to a strong depolarization of the membrane potential and decrease of ATP levels. The derivative also interfered with the cell cycle of Leishmania, inducing a programmed cell death-like mechanism and affecting DNA replication. Further immunomodulatory studies demonstrated that the compound eliminates amastigotes via an independent activation of the host cell, with decrease levels of IL-10, TNF and MCP-1. Additionally, this derivative caused no hemolytic effects in murine erythrocytes and could be considered promising for future lead studies.
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https://observatorio.fm.usp.br/handle/OPI/32026
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Coleções
Artigos e Materiais de Revistas Científicas - IMT
Artigos e Materiais de Revistas Científicas - LIM/49