Antiparasitic Activity of Narciclasine and Evaluation of Its Effects on Plasma Membrane and Mitochondria of .

The EtOAc extract from bulbs of (Amaryllidaceae) exhibited antiprotozoal activity against and afforded the alkaloids narciclasine (), 7-deoxynarciclasine (), and narciclasine-4-O-β-D-xylopyranoside (). studies showed adequate predictions for drug-likeness for alkaloids and , with adherence to Lipinski's rules of five and no alerts for PAINS. When tested against clinical forms of , alkaloid displayed effectiveness with IC values of 17.1 μM (trypomastigotes) and 8.2 μM (amastigotes), with no mammalian cytotoxicity for NCTC cells (CC > 200 μM), similar to the standard drug benznidazole. Alkaloid exhibited moderate activity against intracellular amastigotes (IC = 64.6 μM) and no activity to trypomastigotes, whereas was inactive against both forms of the parasite. These results suggested that free hydroxyl groups at the C-7 and C-4 positions are involved in the potency of the alkaloids. Considering the most potent and selective compound, the lethal action of alkaloid was investigated against extracellular forms (trypomastigotes). Using the fluorescent probe Sytox Green, it was observed that alkaloid presented a dual effect in the plasma membrane at different concentrations from a noninterfering action (at the IC) to a significant alteration in the membrane permeability (IC). At all tested concentrations, alkaloid induced a dose-dependent depolarization of the mitochondrial membrane potential, leading to the lethal effect on . These results suggest alkaloid as a new hit compound, eliminating both clinical forms of the parasite and successful drug-like parameters for an oral candidate for Chagas disease.