Acetogenins from Porcelia macrocarpa (Annonaceae) display activity against Trypanosoma cruzi by alterations in plasma membrane electric and mitochondrial membrane potentials

Porcelia macrocarpa (Warming) R. E. Fries (Annonaceae) is a specie found in the Atlantic Forest and Cerrado regions of Brazil.1 Previous studies by our group have shown the anti-Trypanosoma cruzi activity of acetylene acids from the seeds and flowers from this plant.2,3 As part of a drug discovery program aimed at the identification of anti-T. cruzi metabolites from Brazilian flora, four acetogenins (1 – 4) were isolated from the seeds of P. macrocarpa and were identified by NMR and HRESIMS. The new compounds 1 and 2 displayed activity against the trypomastigote (IC50 = 0.4 and 3.6 M) and amastigote (IC50 = 23.0 and 27.7 M) forms. A structurally related known compound 3 showed less potency to the amastigotes, with an IC50 value of 58 M, 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 (ROS) production, and (iv) mitochondrial membrane potential (ΔΨm). The obtained results indicated that compounds 1 and 2 depolarize plasma membranes affecting ΔΨp and ΔΨm, and contributing to the observed cellular damages and disturbing the bioenergetic system.4 Therefore, these results suggest that the depolarization of both the plasma membrane and mitochondrial membrane potential of T. cruzi may be the result of the inhibitory activity of acetogenins 1 and 2. In silico studies of pharmacokinetics and toxicity (ADMET) properties predicted that all compounds were non-mutagenic, non-carcinogenic, non-genotoxic, and weak hERG blockers5. Additionally, the multi-parametric prediction indicated that none of the analyzed compounds contain PAINS sub-structures. Consequently, there is a low probability that their biological activities are artifacts caused by reactivity or colloidal aggregation. Thus, compounds 1 and 2 represent interesting scaffolds for synthesis of derivatives with potent and selective activity against T. cruzi and could be selected to future experimental preclinical assays against Chagas disease.