AUTHOR=Albuquerque Kelly Cristina Oliveira de , Veiga Andreza do Socorro Silva da , Silveira Fernando Tobias , Campos Marliane Batista , Costa Ana Paula Lima da , Brito Ananda Karolyne Martins , Melo Paulo Ricardo de Souza , Percario Sandro , Molfetta Fábio Alberto de , Dolabela Maria Fâni 

TITLE=Anti-leishmanial activity of Eleutherine plicata Herb. and predictions of isoeleutherin and its analogues

JOURNAL=Frontiers in Chemistry

VOLUME=12

YEAR=2024

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2024.1341172

DOI=10.3389/fchem.2024.1341172

ISSN=2296-2646

ABSTRACT=<p><bold>Introduction:</bold> Leishmaniasis is caused by protozoa of the genus <italic>Leishmania</italic>, 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 <italic>in vitro</italic> anti-leishmanial potential of the extract, fractions, and isoeleutherin from <italic>Eleutherine plicata</italic>, as well as the <italic>in silico</italic> interactions of isoeleutherin and its analogs with Trypanothione Reductase (TR), in addition to predicting pharmacokinetic parameters.</p><p><bold>Methods:</bold> From the ethanolic extract of <italic>E. plicata</italic> (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.</p><p><bold>Results and Discussion:</bold> The extract and its fractions were not active against the promastigote form (IC<sub>50</sub> &gt; 200 μg/mL), while isoeleutherin was active (IC<sub>50</sub> = 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.</p>