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

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.

An in silico molecular modeling approach of halolactone derivatives as potential inhibitors for human immunodeficiency virus type-1 reverse transcriptase enzyme.

Acquired Immune Deficiency Syndrome (AIDS) is an infectious disease caused by Human Immunodeficiency Virus (HIV) infection and its replication requires the Reverse Transcriptase (RT) enzyme. RT plays a key role in the HIV life cycle, making it one of the most important targets for designing new drugs. Thus, in order to increase therapeutic options against AIDS, halolactone derivatives (D-halolactone) that have been showed as potential non-nucleoside inhibitors of the RT enzyme were studied. In the present work, a series of D-halolactone were investigated by molecular modeling studies, combining Three-dimensional Quantitative Structure-Activity Relationship (3 D-QSAR), molecular docking and Molecular Dynamics (MD) techniques, to understand the molecular characteristics that promote biological activity. The internal and external validation parameters indicated that the 3 D-QSAR model has good predictive capacity and statistical significance. Contour maps provided useful information on the structural characteristics of compounds for anti-HIV-1 activity. The docking results showed that D-halolactone present good complementarity by the RT allosteric site. In MD simulations it was observed that the formation of enzyme-ligand complexes were favorable, and from the free energy decomposition it was found that Leu100, Val106, Tyr181, Try188, and Trp229 are key residues for stabilization in the enzymatic site. Thus, the results showed that the proposed models can be used to design promising HIV-1 RT inhibitors. Communicated by Ramaswamy H. Sarma.