Banca de DEFESA: LUCAS CARUSO ARAUJO BEZERRA

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : LUCAS CARUSO ARAUJO BEZERRA
DATE: 26/02/2021
TIME: 09:00
LOCAL: Vídeo conferência
TITLE:

Design, Synthesis and Biological Evaluation of New Chalcones as Potential Anti-Prion Agents

KEY WORDS:

Prion disease, Buchwald-Hartwig, N-arylation.

PAGES: 181
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SPECIALTY: Síntese Orgânica
SUMMARY:

The diseases related to protein misfolding are part of a group of debilitating, degenerative,
progressive, fatal and still intractable neurological disorders. In prion disease, a normal prion
protein (PrPC) is converted to infectious isoforms (PrPSc) rich in β-sheets, with difficulty to be
degraded by proteases and prone to form aggregated fibrillar responsible for the neurotoxicity
of the pathogenic isoform. Although many compounds have shown to inhibit the process of
conversion to PrPSc, until this moment there is no effective therapy for this disorder, since most
of the substances studied in vitro have unfavorable pharmacokinetic profile. This study
proposes the synthesis of five series (Series A, B, C, D and E) of chalcones, based on the J8
prototype, developed as possible anti-prion compounds capable of acting as a chemical
chaperone in the conformational stabilization of the non-infecting PrPC isoform, preventing the
formation of PrPSc. The first series (Series A) of compounds was fully synthesized with
satisfactory yields through Claisen-Schmidt condensation followed by the Buchwald-Hartwig
cross-coupling reaction. Of the seven chalcones synthesized for series A, four of them presented
an excellent biological profile, managing to inhibit the interconversion in vitro of PrPC in PrPSc
by up to 80% in the concentration of 10 M, whose values surpassed those obtained for the
prototype J8. Some final compounds from series B, C and E have already been synthesized,
demonstrating that the synthetic route used is efficient, while the synthetic development of
series D is interrupted in the second to last key-intermediate. The compounds of all series were
subjected to in silico studies of molecular docking and enabled a better understanding of the
binding site of the prion protein and the interaction profile between chalcones and PrP121-231.
Molecular docking studies carried out for D series suggest that these are the most promising
derivatives of all the series, whose binding energy values were better than those found for A
series chalcones, which already have an excellent pharmacological profile.

BANKING MEMBERS:
Presidente - 1700480 - ARTHUR EUGEN KUMMERLE
Interno - 1735975 - CEDRIC STEPHAN GRAEBIN
Interna - 1177598 - ROSANE NORA CASTRO
Externa à Instituição - MARIA LETÍCIA DE CASTRO BARBOSA - UFRJ
Externo à Instituição - VAGNER DANTAS PINHO