Cancer is a multifactorial organic dysfunction for which great efforts are being devoted in searching for new treatments and therapeutic adjuvants. Annona muricata is a fruit that has promising activity against several types of cancer, as it contains acetogenins, the metabolite group associated with this action. Thus, the objective of this study was to evaluate, in experimental models, the toxic behavior of an extract and fraction rich in acetogenins from A. muricata seeds and study the acetogenin, Annonacin, in silico. Phytochemical characterization was made by thin layer chromatography, spectroscopy in the infrared region and nuclear magnetic resonance. Toxicity was evaluated by tests of Allium cepa and Artemia salina, and in silico studies using the SwissDock servers DockThor, PharmMapper, ADMETLab, PreADME, Osiris and ProTox. The extract and fraction showed genotoxic activity against meristematic cells of A. cepa, reducing the mitotic index; however, the extract produced great deleterious effects on the system, even causing cell necrosis. In A. Saline, the extract was more toxic than the fraction, but both samples were considered toxic. Annonacin was effectively linked to complex I, and presented different activities regarding toxicity. Thus, the results of this study are promising, highlighting the anticancer potential of acetogenins.

O presente trabalho realizou estudos in silico com o objetivo de predizer as atividades farmacocinéticas, toxicológicas e biológicas de alcaloides isolados de Geissospermum laeve. Os desenhos das moléculas e análises físico-químicas foram feitas no ChemSketch e Chemicalize.org, o comportamento farmacocinético e toxicidade foram realizadas  por comparação nos programas PreADMET  e  PASS  online. Os resultados descrevem que as moléculas demonstram bom comportamento farmacocinético e biodisponibilidade, com destaque para a Geissosquizina que apresenta alta permeabilidade gastrointestinal, depuração aceitável, sendo metabolizada pela CYP 3A4 e maior interação com receptotres-alvos. A Pereirina e Vellosiminol apresentaram atividades sobre neuroreceptores, enquanto que a Flavopererina demostrou atividades de modulação enzimática, dessa forma essas moléculas destacaram-se quanto às atividades biológicas apresentadas. Todas as substancias se apresentaram tóxicas e mutagênicas, sendo necessários estudos aprofundados que auxiliem a elucidação do índice de seletividade das mesmas. Ao considerar os aspectos farmacocinéticos, toxicológicos e biológicos destacamos que a Pereirina e o Vellosiminol apresentam resultados mais promissores.

This study evaluated the genotoxicity of Ethanol Extract (EEEp), Dichloromethane Fraction (FDCMEp) and isoeleutherin isolated from Eleutherine plicata, using the micronucleus test and the impact of structural alterations on toxicity and molecular docking (topoisomerase II and DNA complex). The extract was obtained by maceration and fractionation in a chromatography column. The genotoxicity was evaluated by the micronucleus test in human hepatoma cells (HepG2). Isoeleutherin was the starting molecule in the search for analogues by structural similarity, using the ZINC and e-Molecules databases. Isoeleutherin and analogues were subjected to in silico toxicity prediction, and compounds free of toxicological risks (CP13, CP14, CP17 and isoeleutherin) were selected for molecular docking in Topoisomerase II (PDB: 1ZXM). In the micronucleus test, isoeleutherin was less genotoxic. Among the 22 isoeleutherin analogues there were variations in the toxicity profile. Molecular docking studies showed that the compounds have good complementarity in the active site with important hydrogens bonds. Therefore, the structural changes of isoeleutherin led to the obtaining of a molecule with a lower mutagenic potential, and the CP13 can be considered a prototype compound for the development of new molecules with pharmacological potential.

From Eleutherine plicata, naphthoquinones, isoeleutherine, and eleutherol were isolated, and previous studies have reported the antioxidant activity of these metabolites. The present work evaluated the role of oxidative changes in mice infected with Plasmodium berghei and treated with E. plicata extract, fraction, and isolated compounds, as well as to verify possible oxidative changes induced by these treatments. E. plicata extracts were prepared from powder from the bulbs, which were submitted to maceration with ethanol, yielding the extract (EEEp), which was fractionated under reflux, and the dichloromethane fraction (FDMEp) was submitted for further fractionation, leading to the isolation of isoeleutherine, eleutherine, and eleutherol. The antimalarial activity was examined using the suppressive test, evaluating the following parameters of oxidative stress: trolox equivalent antioxidant capacity (TEAC), thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH). Furthermore, the molecular docking of naphthoquinones, eleutherol, eleutherine, and isoeleutherine interactions with antioxidant defense enzymes was investigated, which was favorable for the formation of the receptor–ligand complex, according to the re-rank score values. Eleutherine and isoeleutherine are the ones with the lowest binding energy for catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx1), showing themselves as possible targets of these molecules in the involvement of redox balance. Data from the present study showed that treatments with E. plicata stimulated an increase in antioxidant capacity and a reduction in oxidative stress in mice infected with P. berghei, with naphthoquinones being responsible for reducing oxidative changes and disease severity.

Este trabalho relata os resultados obtidos no estudo in silico para a predição de atividade biológicas de diterpenos presentes em P. pilosa, relacionando estes resultados as alegações de uso, aspectos farmacocinéticos e toxicológicos. Vários programas foram utilizados para a predição das atividades biológicas, toxicidade, farmacocinética e propriedades físico químicas. Os estudos de predição sugerem que atividade cicatrizante foi relacionada a friedelina, porém este composto parece ser tóxico, possui elevada lipossolubilidade e inibi a CYP. A atividade anti-inflamatória sistêmica foi relacionada a pilosanona A e pilosanol A, ao se analisar os aspectos tóxicos, farmacocinéticos e físico-químicos, pode-se sugerir que o pilosanol A seja mais promissor. A pilosonona B parece ter um efeito anti-durético, contrário a alegação de uso. Os estudos in silico sugerem o potencial antineoplásico de pilosononas A e B, pilosanol A e B, relaciona os efeitos adversos a imunotoxicidade, sendo que todos os compostos avaliados parecem ligar aos receptores de androgênio, pilosanona A e B e o portulide podem interferir na via das prostaglandinas e na clivagem oxidativa de alquilaminas em aldeídos e amônia. O presente estudo corroborou com as alegações de uso cicatrizante e anti-inflamatório de P. pilosa e sugeri que os compostos fiedelina, pilosanona A e pilosanol A estejam envolvidos nestas atividades.