The treatment of leishmaniasis has limitations due to drug toxicity and the increasing resistance of the parasite. In this study, we analyze the role of oxidative stress in the pathogenesis and treatment of leishmaniasis, as well as in new therapeutic alternatives of natural origin. The evasion mechanisms against the host immune response involve surface molecules present in the parasite, which modulate oxidative stress to ensure its survival. Drug treatment requires strict monitoring to minimize adverse reactions and ensure patient safety, as mechanisms such as lipid peroxidation, mitochondrial dysfunction, and depletion of antioxidant defenses are associated with drug toxicity. Plant-derived products with antileishmanial activity impact the parasite’s redox balance, inducing apoptosis and reducing its parasitic load. Most studies are still in preliminary stages, making in vivo assays and clinical studies essential, along with the development of accessible formulations. Oxidative stress is involved in the pathogenesis of leishmaniasis, as Leishmania manipulates the host’s redox balance to survive. It also contributes to drug toxicity, as antimonials and amphotericin B increase reactive oxygen species, causing cellular damage. Several plant-derived compounds have demonstrated antileishmanial activity by modulating oxidative stress and promoting parasite apoptosis. Examples include alkaloids from Aspidosperma nitidum, lignans from Virola surinamensis, flavonoids from Geissospermum vellosii, and triterpenoids such as β-sitosterol. Although these compounds show promising selectivity, most studies remain in preliminary stages, requiring in vivo assays and clinical studies to confirm efficacy and safety, as well as the development of affordable formulations.

Antimalarial treatment is often associated with the resistance developed by Plasmodium which generate ineffective drug treatment. Based on this, the search for therapeutic alternatives is necessary and urgent. This review intends to assess the antimalarial potential of quinones isolated from plants. The search for scientific articles was carried out on the CAPES Journal Portal (PPC), Virtual Health Library (VHL), PUBMED, NCBI and SCIELO, using the following descriptors: quinones and antimalarials. Inclusion criteria were adopted based on studies about quinones isolated from plants and tested against Plasmodium falciparum and Plasmodium berghei. The exclusion criteria were based mainly on articles that tested extracts, fractions and synthesis of quinones obtained from plants and other natural products. A total of 1344 publications were collected for screening (PPC = 5, VHL = 248, PUBMED = 525, NCBI = 462 and SCIELO = 94). From this total, 1280 articles were excluded, with only 64 articles selected for full reading. All benzoquinones were active against P. falciparum. Naphthoquinones were active, inactive and moderately active against the P. falciparum e P berghei. Anthraquinones and anthrones were active and moderately active against P. falciparum. The naphthoquinone 2-acetylnaphtho- [2,3b] -furan-4,9-dione was the most active of all the molecules tested against Plasmodium. Whereas lapachol was the most studied naphthoquinone and structural changes do not seem to contribute to the activity. In summary, quinones are promising as antimalarials, however, need in vivo studies.

The alkaloids isolated from Zanthoxylum rhoifolium have demonstrated great pharmacological potential; however, the toxic profiles of these extracts and fractions are still not well elucidated. This study evaluated the toxicity of the ethanol extract (EEZR) and neutral (FNZR) and alkaloid (FAZR) fractions. Chemical characterization was performed by chromatographic methods: thin-layer chromatography (TLC) and high-performance liquid chromatography coupled with diode array detection (HPLC–DAD). The cytotoxicity of the samples was evaluated in human hepatocellular carcinoma (HepG2) cells using the cell viability method (MTT) and mutagenicity by the Allium cepa assay (ACA). Alkaloids isolated from the species were selected for toxicity prediction using preADMET and PROTOX. The molecular docking of the topoisomerase II protein (TOPOII) was used to investigate the mechanism of cell damage. In the EEZR, FNZR, and FAZR, the presence of alkaloids was detected in TCL and HPLC–DAD analyses. These samples showed a 50% inhibitory concentration (IC₅₀) greater than 400 μg/mL in HepG2 cells. In ACA, time- and concentration-dependent changes were observed, with a significant reduction in the mitotic index and an increase in chromosomal aberrations for all samples. Nuclear sprouts and a micronucleus of the positive control (PC) were observed at 10 µg/mL and in the FAZR at 30 µg/mL; a chromosomal bridge in FNZR was observed at 105 µg/mL, CP at a concentration of 40 µg/mL, and nuclear bud and mitotic abnormalities in the EEZR were observed at 170 µg/mL. The alkaloids with a benzophenanthridine were selected for the in silico study, as structural alterations demonstrated certain toxic effects. Molecular docking with topo II demonstrated that all alkaloids bind to the protein. In summary, the fractionation of Z. rhoifolium did not interfere with toxicity; it seems that alkaloids with a benzophenanthridine nucleus may be involved in this toxicity.

This study aimed to evaluate the anti-leishmania activity of extracts and fractions from stem and leaf of Montrichardia linifera against Leishmania amazonensis. The stem (EES) and leaf (EEL) extracts were obtained by maceration of powders with 96º GL alcohol. The extracts were subjected to exhaustive extraction using a reflux system and solvents of increasing polarity, obtaining 4 fractions for each extract: hexane, dichloromethane, ethyl acetate and methanol. The extracts and fractions were submitted to a phytochemical prospecting study. The antipromastigote activity and cytotoxicity in macrophages (J774) were performed using the cell viability test (MTT). In the extract and fractions of the stem, alkaloids, steroids, terpenes, flavonic heterosides, tannins, polyphenols and saponins were detected. In the extract and fractions of the leaves, coumarins, steroids, terpenes, flavonic heterosides, tannins, polyphenols and saponins were detected. In the anti-leishmania evaluation, the hexane fraction of the leaf (HFL) showed promising activity (IC50=38.56 µg/mL), and the hexane fraction of the stem (HFS) showed moderate activity (CI50=179.3 µg/mL), the extracts and the other fractions were inactive (IC50>200 µg/mL). In the cytotoxicity test, EES and HFS were cytotoxic (CC50 54.82 µg/mL and 26.95 µg/mL, respectively). EEF and HFL showed moderate cytotoxicity (CC50 of 162.7 µg/mL and 347.1 µg/mL). As for the selectivity index, the HFL showed high selectivity (SI=90). In summary, fractionation contributed to increase anti-leishmania activity and the selectivity of HFS, such activity may be related to steroids or terpenes.

Cupuaçu (Theobroma grandiflorum) from the Malvaceae family, has seeds rich in flavonoids. The biological activities of seeds are diverse, however, there are scarce data on these metabolites. The study aimed to evaluate, through in silico methods, the biological, toxicological, and pharmacokinetic potential of metabolites present in the cupuaçu seed. The metabolites hypolaetina 3'-methylether 8-O-β-D glucuronide, theograndin II, hypolaetina 3'-methylether 8-O-β-D 3”-sulfated glucuronide, isoscutellarein 8-0-β-D glucuronide and theograndin I were analysed through Pubchem to search for structures, and PreADMET (pharmacokinetics and toxicity) and PASS online for biological activities (PA >98%). The results demonstrated low human intestinal absorption, in addition to weak to moderate distribution across the blood-brain barrier. All phenolic compounds showed weak to moderate binding to plasma proteins and low permeability in CaCo2 cells, except for isoscutelarein 8-0-β-D glucuronide and hypolaetina 3'-methylether 8-O-β-D glucuronide with moderate permeability, being non-mutagenic. Furthermore, they had the potential to inhibit CYPs, such as CYP-2C9 and CYP-3A4. Also, the structures showed toxicity in Medaka fish, but they did not present toxicity in algae and Daphnia sp. Finally, the molecules presented the following main properties: hemostatic, cardioprotective, and antioxidant action, among others. The compounds presented varied biological activity profiles, but their pharmacokinetic and toxicity were not promising, limiting the potential for developing new drugs. The use of technologies is suggested to transform them into prodrugs, carriers, and the use of molecular modeling. El cupuaçu (Theobroma grandiflorum) de la familia Malvaceae, tiene semillas ricas en flavonoides. Las actividades biológicas de las semillas son diversas, aunque hay escasez de estudios sobre estos metabolitos. El objetivo del estudio fue evaluar, mediante métodos in silico, el potencial biológico, toxicológico y farmacocinético de los metabolitos presentes en las semillas de cupuaçu. Se analizaron los metabolitos: hipolaetina 3'-metiléter 8-O-β-D glucurónido, theograndina II, hipolaetina 3'-metiléter 8-O-β-D glucurónido 3”-sulfatado, isoscutelareína 8-0-β-D glucurónido y theograndina I, utilizando PubChem para buscar las estructuras, PreADMET (farmacocinética y toxicidad) y PASS online para actividades biológicas (PA > 98%). Los resultados de las moléculas mostraron baja absorción intestinal humana, así como distribución débil a moderada en la barrera hematoencefálica. Todos los compuestos fenólicos presentaron una unión débil a moderada a proteínas plasmáticas y baja permeabilidad en células CaCo2, excepto isoscutelareína 8-0-β-D glucurónido y hipolaetina 3'-metiléter 8-O-β-D glucurónido, que presentaron permeabilidad moderada y no fueron mutagénicos. Además, mostraron potencial para la inhibición de CYPs, como CYP-2C9 y CYP-3A4. Las estructuras también presentaron toxicidad en peces Medaka, sin embargo, no mostraron toxicidad en algas y Daphnia sp. En cuanto a las actividades biológicas, las moléculas presentaron propiedades principales como acción hemostática, cardioprotectora, antioxidante, entre otras. Aunque los compuestos mostraron diversos perfiles de actividades biológicas, sus perfiles farmacocinéticos y de toxicidad no fueron prometedores, lo que limita el potencial para el desarrollo de nuevos fármacos. Se sugiere explorar tecnologías como la transformación en profármacos, transportadores y el uso de modelado molecular. O cupuaçu (Theobroma grandiflorum) da família Malvaceae, possui sementes ricas em flavonoides. As atividades biológicas das sementes são diversas, entretanto, há escassez de estudos desses metabólitos. O objetivo do estudo foi avaliar, por métodos in silico, o potencial biológico, toxicológico e farmacocinética de metabólitos presentes na semente do cupuaçu. A análise ocorreu nos metabólitos: hipolaetina 3’-metiléter 8-O-β-D glicuronídeo, theograndina II, hipolaetina 3’-metiléter 8-O-β-D glicuronídeo 3”-sulfatado, isoscutelareína 8-0-β-D glicuronídeo e theograndina I, através do Pubchem para busca das estruturas, PreADMET (farmacocinética e toxicidade) e o PASS online para atividades biológicas (PA >98%). Os resultados das moléculas demonstraram baixa absorção intestinal humana, além de fraca a moderada distribuição na barreira hematoencefálica. Todos os compostos fenólicos apresentaram fraca a moderada ligação a proteína plasmática e baixa permeabilidade em células CaCo2, com exceção da isoscutelareína 8-0-β-D glicuronídeo e da hipolaetina 3’-metiléter 8-O-β-D glicuronídeo com moderada permeabilidade, sendo não mutagênica. Ademais, apresentaram potencial para inibição de CYPs, como a CYP-2C9 e a CYP-3A4. Também, as estruturas apresentaram toxicidade em peixes Medaka, no entanto, não apresentaram toxicidade em algas e Daphnia sp. Enfim, em relação às atividades biológicas, as moléculas apresentaram como principais propriedades: ação hemostática, cardioprotetora, antioxidante, entre outras. Os compostos apresentaram variados perfis de atividades biológicas, mas seus perfis farmacocinéticos e de toxicidade não foram promissores, limitando o potencial para desenvolvimento de novos fármacos, sugere-se a utilização de tecnologias, como...

Based on ethnobotanical studies, the Aspidosperma excelsum was selected due to its highest claim of popular use for malaria and febrile diseases treatments. This species is rich in secondary metabolites as alkaloids and therefore, the aim of this study was to evaluate the pharmacokinetic, toxicological and biological activity of alkaloids isolated from Aspidosperma excelsum by in silico studies. All substances already isolated from this species were submitted to predictive studies of biological, toxicological and pharmacokinetic activities. Predictive studies of biological activities did not attribute the antimalarial activity to pure substances. However, other activities were found, such as: action on central nervous system and antineoplastic activity. In pharmacokinetic terms, many substances showed an inhibitory action on cytochrome P450 (CYP) and many adverse reactions, highlighting actions on the CNS. Also, several alkaloids, being nitrogenous substances, presented mutagenic or genotoxic activities. Thus, it is demonstrated the species potential for biological activities not yet studied, as well as the importance of investigating its pharmacokinetic and toxicological properties, justifying the accomplishment of the present study.