# Discovery of Potential Antileishmanial Compounds Through Phenotypic Screening of an Alkaloid Library

## TL;DR

This study identifies six promising antileishmanial compounds from an alkaloid library that effectively target a parasitic disease with minimal toxicity.

## Contribution

The study introduces six novel isoquinoline-type alkaloids with high antileishmanial efficacy and low cytotoxicity.

## Key findings

- Six isoquinoline-type alkaloids showed strong antileishmanial activity against intramacrophagic amastigotes.
- These compounds exhibited minimal cytotoxicity and a selective index higher than four.
- The protoberberine scaffold was identified as the most promising candidate for drug development.

## Abstract

Visceral leishmaniasis caused by Leishmania donovani is one of the major neglected tropical diseases attributable to parasitic protozoa. In the absence of an effective vaccine, chemotherapy remains the only available therapeutic option. However, current treatments rely on a limited number of drugs that are largely obsolete, highly toxic or require intravenous administration, and their extensive use has led to the emergence of drug resistance. Consequently, the discovery of new antileishmanial agents is an urgent priority. In this study, a commercial library of 449 alkaloids in a high-throughput screening format was evaluated against both axenic bone marrow-derived amastigotes and intramacrophagic amastigotes from mice infected with L. donovani IRFP, a strain engineered to emit infrared fluorescence in its viable form. Six isoquinoline-type alkaloids showed the best antileishmanial efficacy against intramacrophagic amastigotes while exhibiting minimal cytotoxicity toward RAW 264.7 and HepG2 cell lines, with a promising selective index higher than four, and good mouse intestinal tolerance in mouse organoids. Among these compounds, the protoberberine scaffold emerged as the most promising candidate for further drug development.