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Anti-leishmanial activity of Eleutherine plicata Herb. and predictions of isoeleutherin and its analogues.
de Albuquerque, Kelly Cristina Oliveira; da Veiga, Andreza do Socorro Silva; Silveira, Fernando Tobias; Campos, Marliane Batista; da Costa, Ana Paula Lima; Brito, Ananda Karolyne Martins; Melo, Paulo Ricardo de Souza; Percario, Sandro; de Molfetta, Fábio Alberto; Dolabela, Maria Fâni.
Afiliação
  • de Albuquerque KCO; Biotechnology and Biodiversity Postgraduate Program (BIONORTE), Federal University of Pará, Belém, PA, Brazil.
  • da Veiga ADSS; Pharmaceutical Innovation Postgraduate Program, Federal University of Pará, Belém, PA, Brazil.
  • Silveira FT; Leishmaniasis Laboratory, Evandro Chagas Institute, Ananindeua, PA, Brazil.
  • Campos MB; Leishmaniasis Laboratory, Evandro Chagas Institute, Ananindeua, PA, Brazil.
  • da Costa APL; Laboratory of Molecular Modeling, Institute of Exact and Natural Sciences, Federal University of Pará, Belém, PA, Brazil.
  • Brito AKM; Faculty of Pharmacy, Federal University of Pará, Belém, PA, Brazil.
  • Melo PRS; Pharmaceutical Sciences Postgraduate Program, Federal University of Pará, Belém, PA, Brazil.
  • Percario S; Biotechnology and Biodiversity Postgraduate Program (BIONORTE), Federal University of Pará, Belém, PA, Brazil.
  • de Molfetta FA; Laboratory of Molecular Modeling, Institute of Exact and Natural Sciences, Federal University of Pará, Belém, PA, Brazil.
  • Dolabela MF; Biotechnology and Biodiversity Postgraduate Program (BIONORTE), Federal University of Pará, Belém, PA, Brazil.
Front Chem ; 12: 1341172, 2024.
Article em En | MEDLINE | ID: mdl-38510811
ABSTRACT

Introduction:

Leishmaniasis is caused by protozoa of the genus Leishmania, classified as tegumentary and visceral. The disease treatment is still a serious problem, due to the toxic effects of available drugs, the costly treatment and reports of parasitic resistance, making the search for therapeutic alternatives urgent. This study assessed the in vitro anti-leishmanial potential of the extract, fractions, and isoeleutherin from Eleutherine plicata, as well as the in silico interactions of isoeleutherin and its analogs with Trypanothione Reductase (TR), in addition to predicting pharmacokinetic parameters.

Methods:

From the ethanolic extract of E. plicata (EEEp) the dichloromethane fraction (FDEp) was obtained, and isoeleutherin isolated. All samples were tested against promastigotes, and parasite viability was evaluated. Isoeleutherin analogues were selected based on similarity in databases (ZINK and eMolecules) to verify the impact on structural change. Results and

Discussion:

The extract and its fractions were not active against the promastigote form (IC50 > 200 µg/mL), while isoeleutherin was active (IC50 = 25 µg/mL). All analogues have high intestinal absorption (HIA), cell permeability was moderate in Caco2 and low to moderate in MDCK. Structural changes interfered with plasma protein binding and blood-brain barrier permeability. Regarding metabolism, all molecules appear to be CYP3A4 metabolized and inhibited 2-3 CYPs. Molecular docking and molecular dynamics assessed the interactions between the most stable configurations of isoeleutherin, analogue compound 17, and quinacrine (control drug). Molecular dynamics simulations demonstrated stability and favorable interactions with TR. In summary, fractionation contributed to antileishmanial activity and isoleutherin seems to be promising. Structural alterations did not contribute to improve pharmacokinetic aspects and analogue 17 proved to be more promising than isoeleutherin, presenting better stabilization in TR.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Front Chem Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Brasil País de publicação: Suíça
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Front Chem Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Brasil País de publicação: Suíça