# In Vitro Leishmanicidal Effect of Silibinin: Disrupting Redox Balance via Trypanothione Reductase Inhibition

## TL;DR

Silibinin, a compound from Silybum marianum, shows strong antiparasitic effects against Leishmania infantum by disrupting its redox balance.

## Contribution

This study demonstrates silibinin's leishmanicidal activity via trypanothione reductase inhibition and redox disruption.

## Key findings

- Silibinin inhibits Leishmania infantum promastigote proliferation with an IC50 of 416.7 μM.
- It effectively targets intracellular amastigotes with an EC50 of 0.7 μM and a high selectivity index of 242.
- Silibinin disrupts redox balance by inhibiting trypanothione reductase, leading to ROS accumulation and parasite death.

## Abstract

Visceral leishmaniasis,
caused by the parasite Leishmania
infantum, is a life-threatening disease with limited
therapeutic options that are often associated with toxicity and resistance.
In this study, we investigated the in vitro leishmanicidal
effects of silibinin, a key flavonolignan from Silybum
marianum, against both the promastigote and intracellular
amastigote forms of L. infantum. Mechanistically,
silibinin inhibits trypanothione reductase (TR), disrupting the redox
balance in the parasite and causing cell death. Silibinin concentration-dependently
inhibited promastigote proliferation (IC50 of 416.7 μM)
with potent activity against intracellular amastigotes (EC50 of 0.7 μM) and a high selectivity index (242), indicating
its strong therapeutic potential and nontoxicity to macrophages. Importantly,
silibinin disrupts the L. infantum redox
balance by inhibiting TR activity, which increases the reactive oxygen
species (ROS) levels to kill the parasite. ROS accumulation and the
inhibition of parasite proliferation were significantly correlated
(Pearson correlation coefficient of 0.9895). Molecular docking confirmed
that silibinin binds to the catalytic site of TR, corroborating its
role in ROS-mediated parasite death. Furthermore, in silico ADMET analysis revealed that silibinin has favorable pharmacokinetic
properties for oral administration. Finally, in vitro and in silico studies indicated that silibinin
inhibits TR, a key enzyme in Leishmania redox homeostasis,
to exert antileishmanial effects.