Antitrypanosomal Activity of Acetogenins Isolated from the Seeds of <i>Porcelia macrocarpa</i> Is Associated with Alterations in Both Plasma Membrane Electric Potential and Mitochondrial Membrane Potential

As part of a drug discovery program aimed at the identification of anti-Trypanosoma cruzi metabolites from Brazilian flora, four acetogenins (1–4) were isolated from the seeds of Porcelia macrocarpa and were identified by NMR spectroscopy and HRESIMS. The new compounds 1 and 2 displayed activity against the trypomastigote (IC50 = 0.4 and 3.6 μM) and amastigote (IC50 = 23.0 and 27.7 μM) forms. The structurally related known compound 3 showed less potency to the amastigotes, with an IC50 value of 58 μM, while the known compound 4 was inactive. To evaluate the potential mechanisms for parasite death, parameters were evaluated by fluorometric assays: (i) plasma membrane permeability, (ii) plasma membrane electric potential (ΔΨp), (iii) reactive oxygen species production, and (iv) mitochondrial membrane potential (ΔΨm). The results obtained indicated that compounds 1 and 2 depolarize plasma membranes, affecting ΔΨp and ΔΨm and contributing to the observed cellular damage and disturbing the bioenergetic system. In silico studies of pharmacokinetics and toxicity (ADMET) properties predicted that all compounds were nonmutagenic, noncarcinogenic, nongenotoxic, and weak hERG blockers. Additionally, none of the isolated acetogenins 1–4 were predicted as pan-assay interference compounds