# Haemanthidine-Containing Alkaloid Fraction from Crinum scabrum as a Natural Therapeutics for Chagas Disease

## TL;DR

A natural compound from Crinum scabrum shows strong potential as a treatment for Chagas disease with low toxicity.

## Contribution

Identification of haemanthidine-containing alkaloids as potent and selective anti-Chagas agents with validated mechanisms of action.

## Key findings

- Fraction III of C. scabrum showed potent activity against intracellular T. cruzi amastigotes with high selectivity.
- Purified compounds C1/C2 and C3 exhibited strong efficacy against amastigotes with low cytotoxicity.
- Computational studies validated inhibition of T. cruzi GAPDH and Cruzain as key mechanisms of action.

## Abstract

Crinum
scabrum, an underexplored
species and potential source of the bioactive alkaloid haemanthidine,
was investigated. A crude methanolic extract was prepared and subjected
to acid–base extraction to obtain an alkaloid-enriched fraction.
Four alkaloids were isolated and purified; structural characterization
via 1H and 13C NMR spectroscopy, coupled with
literature comparison, identified them as haemanthidine/6-epi-haemanthidine (C1/2), crinamine
(C3), and hamayne (C4). The extracts and
purified compounds were screened against Trypanosoma
cruzi (amastigote and trypomastigote forms) and Vero
host cells. Fraction III exhibited potent activity against intracellular
amastigotes (IC50 = 0.88 ± 0.08 μg mL–1), comparable to benznidazole (IC50 = 0.75 ± 0.07
μg mL–1), with exceptional selectivity (SI
> 568.2). Critically, no extract and fractions inhibited trypomastigotes
(IC50 > 500 μg mL–1), mirroring
benznidazole’s stage-specific limitation. For intracellular
amastigotes, purified C1/C2 (IC50 = 6.05 ±
0.53 μM) and C3 (IC50 = 5.79 ±
0.17 μM) showed the highest potency. All compounds exhibited
low cytotoxicity (CC50 > 200), yielding exceptional
selectivity
indices (SI > 80). Additionally, through integrated computational
target prediction (PharmMapper) and molecular docking simulations,
the study identified and validated the inhibition of T. cruzi GAPDH and Cruzain as key mechanisms of action
for the bioactive alkaloids. These findings position C. scabrum alkaloid-enriched fraction as a promising
low-toxicity alternative for chronic Chagas disease, warranting in vivo validation and metabolomic profiling to elucidate
bioactive cofactors.