Banca de DEFESA: DAIANA DE FATIMA PORTELLA FRANCO

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
DISCENTE : DAIANA DE FATIMA PORTELLA FRANCO
DATA : 13/03/2020
HORA: 09:30
LOCAL: PQ sala 50
TÍTULO:

SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF NEW 3-AMINO-1,2,4-TRIAZOLES AS ENZYME INHIBITORS INVOLVED IN ALZHEIMER'S DISEASE

PALAVRAS-CHAVES:

Alzheimer, acetylcholinesterase, chelating and 1,2,4-triazoles

PÁGINAS: 270
GRANDE ÁREA: Ciências Exatas e da Terra
ÁREA: Química
SUBÁREA: Química Orgânica
ESPECIALIDADE: Síntese Orgânica
RESUMO:

Alzheimer’s Disease is a chronic neurodegenerative disorder, capable of provoking progressive
loss of memory and other functions. It is a complex disease, multifactorial and with an unknown
origin. Characterized by decrease of cholinergic neuronal activity; deposition of anomalous
protein aggregates; neuroinflammation; disfunction of metallic homeostasis; and oxidative
stress. Currently, the treatment is based on symptomatic control, mainly with cholinesterase
inhibitors. Due the unsuccessful clinical results of most of the drug candidates against
Alzheimer’s Disease, the strategy based on multitargets compounds, has been being very
relevant in this context. Therefore, the objective of this paper is synthesis and pharmacological
evaluation of a hybrid series of 1,3-amino-1,2,4-triazoles, the multitarget compounds (89a;90aab) for Alzheimer’s Disease treatment, based on non-classic isosteric exchange of triazines for
3-amino-1,2,4-triazoles; and molecular hybridization with the classic drug donepezil. The
compounds containing 1,3-amino-1,2,4-triazoles nucleus were obtained through the
regioselective synthesis from N-acyl-2-methyl-isothiourea N-Boc using microwave irradiation
(Y= 45% - 88%). Followed by alkylation reactions (37% - 79%); amination (35% - 66%); and
deprotection of Boc group (85% - 96%), obtaining the final products (89a;90a-aa), which were
all characterized by RMN 1H and 13C. The compounds 90p (R1= NO2) (AChE; IC50 = 0,386;
IS= 5,86) and the compound 90v (R1= Bz) (BChE; IC50 = 0,416, IS= 3,66) presented the highest
inhibitory activities to the cholinesterases AChE and BuChE respectively, in addition, presented
mixed inhibition profile in the assays of enzymatic kinetics. Furthermore, the molecular
docking has showed the mainly interactions between the compounds (89a and 90p) with the
residue W86, W286 and Y124 of AChE active site. However, the compounds (89a; 90a-ab)
have not showed antioxidant activities in DPPH assay. In the end, spectroscopic results of
fluorescent emission indicate the formation of the triazole complex (89a; 90b; 90r) with
metallic ions, and the compound with best performance complexed with all metallic ions: Zn2+,
Cu2+, Al3+, Fe3+. The results were promising, because were obtained more active compounds
than the prototype, including the capacity of complexing with metallic ions, important
properties to defeat Alzheimer. As a perspective, the compounds (89a; 90a-ab) will be send to
assays of βA aggregation inhibition and neurotoxicity; and the exploration of new series varying
substituents in benzylpiperazine group.

MEMBROS DA BANCA:
Presidente - 1700480 - ARTHUR EUGEN KUMMERLE
Interna - 387189 - AUREA ECHEVARRIA AZNAR NEVES LIMA
Interna - 1979542 - RENATA BARBOSA LACERDA
Interna - 1177598 - ROSANE NORA CASTRO
Externo à Instituição - VAGNER DANTAS PINHO
Externa à Instituição - LUANA DA SILVA MAGALHÃES FOREZI - UFF
Externo à Instituição - SÉRGIO PINHEIRO - UFF