Banca de DEFESA: LUCAS DIEGO PEREIRA BENTO

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : LUCAS DIEGO PEREIRA BENTO
DATE: 23/02/2026
TIME: 14:00
LOCAL: https://meet.google.com/rud-jtyq-xqs
TITLE:

Synthesis, characterization, and in vitro, in silico, and in vivo evaluation of zinc 390718 analogs as acetylcholinesterase and butyrylcholinesterase inhibitors for the treatment of Alzheimer's disease.

KEY WORDS:

Alzheimer's disease, Diaryl ketones, Cholinesterase inhibitors

PAGES: 153
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SUMMARY:

    Alzheimer’s disease (AD), characterized by Alois Alzheimer in 1907, is a progressive, degenerative, and fatal disorder that begins in brain regions related to memory, spreads throughout the brain, and ultimately culminates in death. It represents the leading cause of cognitive decline in the elderly, with prevalence increasing from 0.7% among individuals aged 60–64 years to approximately 40% in those aged 90–95 years. Moreover, more than 10 million new cases of dementia arise annually worldwide, driven by population aging. Given the limitations of current therapies, the search for new cholinesterase inhibitors with greater selectivity, prolonged efficacy, and lower toxicity has been intense, employing Medicinal Chemistry strategies such as molecular modeling, rational drug design, targeted synthesis, and biochemical assays. In this study, 24 diarylketones inspired by the prototype ZINC390719 were synthesized via the Claisen–Schmidt method, incorporating Medicinal Chemistry principles such as conformational rigidification and ring bioisosterism to improve affinity and selectivity. Docking studies revealed high binding affinities for AChE (−7.4 to −9.2 kcal/mol) and BuChE (−6.8 to −8.6 kcal/mol), with relevant π–π and hydrophobic interactions with key residues of the active sites. The anticholinesterase activity of the synthesized compounds was evaluated using the Ellman method, where the compounds 13 and 23 exhibited satisfactory dual inhibition, with IC₅₀ values lower than those of ZINC390718. Compound 13 demonstrated greater potency, showing lower IC₅₀ values for both AChE and BChE compared to compound 23. In vivo assays in AD models showed that compound 13 promoted significant neuroprotective effects, including increased neuronal density in the hippocampus, positive modulation of the astrocytic response, and reduction of histopathological alterations associated with neurodegeneration. These findings indicate that the evaluated diarylketones constitute promising candidates for the development of new therapeutic approaches for Alzheimer’s disease.

BANKING MEMBERS:
Externo ao Programa - 1421228 - LUCAS RAPOSO CARVALHO
Presidente - 1222623 - MARCELO SIQUEIRA VALLE
Externo à Instituição - THIAGO MOREIRA PEREIRA