Avaliação in silico e in vivo do perfil de metabolismo e toxicidade hepática de alcaloides β-carbolínicos sintéticos com prévia atividade antimalárica

• Autor(a) principal: Javert Pereira, Jorddan
• Data de Publicação: 2024
• Outros Autores: Soares da Silva, Yulla, de Moura Alves, Fernanda, Martins Bellei, Pedro, Ribeiro Viana, Gustavo Henrique, Katiani Gorza Scopel, Kézia, Pires de Andrade, Bruno, Corrêa Bezerra Bellei, Jessica
• Tipo de documento: Artigo
• Idioma: por
• Título da fonte: HU Revista (Online)
• Texto Completo: https://periodicos.ufjf.br/index.php/hurevista/article/view/42343
• topic: Pharmacokinetics; Biochemistry; Cytochrome P-450; In silico modeling; Toxicity; Farmacocinética; Bioquímica; Citocromo P-450; Modelagem por Computador; Toxicidade

Introduction: Malaria continues to be a serious global public health problem, given the high annual morbidity and mortality rates. It is caused by protozoa of the genus Plasmodium, with P. falciparum responsible for most serious cases and deaths. Treatment is based on the use of drugs such as chloroquine or artemisinin-based combined therapy, however, the resistance of parasites to available drugs has become an alarming reality. Therefore, it is necessary to study and develop new drugs with antimalarial activity. Objective: To evaluate the metabolism and liver toxicity profile of three β-carboline alkaloids (1, 2 and 3) selected in a previous study, which showed antimalarial activity in vitro and in vivo. Material and methods: This is a study with a qualitative and quantitative approach with an experimental and analytical nature. In silico analysis of the metabolism and toxicity properties of alkaloids was carried out using the SMILES notation through the AdmetSAR 2.0 program. Biochemical analysis of aspartate aminotrasferase (AST) and alanine aminotransferase (ALT) was also carried out in the serum of mice of the C57BL/6 lineage, treated with alkaloids or chloroquine, with subsequent statistical analysis using ANOVA and Tukey tests. Results: In the in silico analysis, the prediction of low hepatotoxic potential for alkaloids 1 and 2 was observed, and this result was corroborated by the ALT dosage, which presented results similar to those of the control group. Alkaloid 3, however, presented contrasting data, indicating hepatotoxic potential in in silico prediction, however, low potential in in vivo analysis, with ALT values ​​also close to the control group. All alkaloids under study showed potential for drug interactions. Conclusion: All alkaloids showed promising metabolic and toxicity parameters and could be good adjuvants for malaria pharmacotherapy. However, these results need to be confirmed to proceed the molecules in preclinical studies.