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

Author(s)

Gomes, Kaio S. ; Costa-Silva, Thais A. ; Borges, Warley S. ; Andrade, Beatriz A. ; Ferreira, Dayana A. ; Tempone, Andre G. ; Ryffel, David ; Sarlah, David ; Lago, Joao Henrique G.

• Document type: Journal article
• Source: ACS OMEGA; v. 10, n. 3, p. 8-pg., 2025-01-14.

Abstract

The EtOAc extract from bulbs of Hymenocallis littoralis (Amaryllidaceae) exhibited antiprotozoal activity against Trypanosoma cruzi and afforded the alkaloids narciclasine (1), 7-deoxynarciclasine (2), and narciclasine-4-O-beta-D-xylopyranoside (3). In silico studies showed adequate predictions for drug-likeness for alkaloids 1 and 2, with adherence to Lipinski ' s rules of five and no alerts for PAINS. When tested against clinical forms of T. cruzi, alkaloid 1 displayed in vitro effectiveness with IC50 values of 17.1 mu M (trypomastigotes) and 8.2 mu M (amastigotes), with no mammalian cytotoxicity for NCTC cells (CC50 > 200 mu M), similar to the standard drug benznidazole. Alkaloid 3 exhibited moderate activity against intracellular amastigotes (IC50 = 64.6 mu M) and no activity to trypomastigotes, whereas 2 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 1 was investigated against extracellular forms (trypomastigotes). Using the fluorescent probe Sytox Green, it was observed that alkaloid 1 presented a dual effect in the plasma membrane at different concentrations from a noninterfering action (at the IC50) to a significant alteration in the membrane permeability (IC90). At all tested concentrations, alkaloid 1 induced a dose-dependent depolarization of the mitochondrial membrane potential, leading to the lethal effect on T. cruzi. These results suggest alkaloid 1 as a new hit compound, eliminating both clinical forms of the parasite and successful in silico drug-like parameters for an oral candidate for Chagas disease. (AU)

• FAPESP's process: 23/12447-1 - Searching for specialized metabolites from Brazilian floristic biodiversity as drug candidates for neglected tropical diseases
• Grantee: João Henrique Ghilardi Lago
• Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants
• FAPESP's process: 19/13906-4 - Discovering new drug leads against Chagas Disease Based on Brazilian bioactive plant molecules
• Grantee: João Henrique Ghilardi Lago
• Support Opportunities: Regular Research Grants