Planejamento de novos derivados da tacrina e vortioxetina contendo selênio com potencial terapêutico para a doença de Alzheimer e o Transtorno Depressivo maior

Abstract

Alzheimer's Disease (AD) and Major Depressive Disorder (MDD) pose serious challenges both clinically and in society due to their increasing incidence, negative impact on quality of life, and limited treatment options. In this study, selenated compounds derived from tacrine and vortioxetine, representative medications for AD and MDD, respectively, were designed, analyzed computational methods, and synthesized. The tacrine-derived compounds (T12–T14) exhibited greater conformational stability than the parent compound and showed no evidence of hepatotoxicity compared to the original tacrine. Furthermore, they demonstrated good theoretical permeability, blood-brain barrier crossing capacity, and reduced interaction with CYP2D6, which reduces the chances of interactions with other medications and the formation of toxic metabolites. The vortioxetine-derived compounds (V8, V9, V13, and V14) demonstrated higher binding affinities than the parent molecule for 5-HT1B and 5-HT3A receptors, in addition to beneficial interactions with MAO-A and MAO-B. Metabolic prediction revealed a decrease in phase I metabolism, indicating a greater potential for bioavailability compared to the currently available and widely used vortioxetine. Molecular dynamics simulations validated the robustness of the ligand-receptor complexes, and the findings collectively support the theory that the addition of selenated fragments may result in safer and more effective therapeutic alternatives. This research demonstrates the synergy between the tacrine and vortioxetine prototypes, highlighting the potential for advancing multi-targeted drugs targeting neurodegenerative and psychiatric disorders.