(-)-5-Demethoxygrandisin B a New Lignan from Leaves: Evaluation of the Leishmanicidal Activity by In Vitro and In Silico Approaches.

Leishmaniasis is a complex disease caused by infection with different parasites. The number of medications used for its treatment is still limited and the discovery of new drugs is a valuable approach. In this context, here we describe the in vitro leishmanicidal activity and the in silico interaction between trypanothione reductase (TryR) and (-)-5-demethoxygrandisin B from the leaves of (Rol.) Warb. The compound (-)-5-demethoxygrandisin B was isolated from leaves, a plant found in the Brazilian Amazon, and it was characterized as (7R,8S,7'R,8'S)-3,4,5,3',4'-pentamethoxy-7,7'-epoxylignan. In vitro antileishmanial activity was examined against , covering both promastigote and intracellular amastigote phases. Cytotoxicity and nitrite production were gauged using BALB/c peritoneal macrophages. Moreover, transmission electron microscopy was applied to probe ultrastructural alterations, and flow cytometry assessed the shifts in the mitochondrial membrane potential. In silico methods such as molecular docking and molecular dynamics assessed the interaction between the most stable configuration of (-)-5-demethoxygrandisin B and TryR from (PDB ID 2JK6). As a result, the (-)-5-demethoxygrandisin B was active against promastigote (IC 7.0 µM) and intracellular amastigote (IC 26.04 µM) forms of , with acceptable selectivity indexes. (-)-5-demethoxygrandisin B caused ultrastructural changes in promastigotes, including mitochondrial swelling, altered kDNA patterns, vacuoles, vesicular structures, autophagosomes, and enlarged flagellar pockets. It reduced the mitochondria membrane potential and formed bonds with important residues in the TryR enzyme. The molecular dynamics simulations showed stability and favorable interaction with TryR. The compound targets mitochondria via TryR enzyme inhibition.