Banca de DEFESA: GABRIELA ALVES DE SOUZA

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
DISCENTE : GABRIELA ALVES DE SOUZA
DATA : 21/11/2018
HORA: 10:00
LOCAL: Departamento de Química sala 50
TÍTULO:

Synthesis of Alkylamino-Coumarin Compounds Designed as Acetylcholinesterase and β-Amyloid Plate Aggregation Inhibitors for the Treatment of Alzheimer's Disease

PALAVRAS-CHAVES:

Coumarin, Alzheimer's Disease, AChE Inhibitors, Aβ Plate Aggregation Inhibitors.

PÁGINAS: 183
GRANDE ÁREA: Ciências Exatas e da Terra
ÁREA: Química
SUBÁREA: Química Orgânica
ESPECIALIDADE: Síntese Orgânica
RESUMO:

Alzheimer's disease (AD) is a neurodegenerative disorder that causes a general, progressive and irreversible deterioration of several cognitive functions (memory, attention, concentration, language, thought, among others), making it difficult to perform daily activities. The use of hybrid compounds for the treatment of AD with inhibitory potential for more than one target, such as the acetylcholinesterase enzyme (AChE) and the aggregation of β-amyloid plaques (Aβ), is very promising, due to the possibility of inhibiting simultaneously two or more factors that contribute to the establishment and evolution of the disease. AChE modules the levels of the neurotransmitter acetylcholine (ACh) in the synaptic cleft, factor that is involved in the learning and memory processes. The aggregation of Aβ plaques isone of the main causes for neuronal death. Thus, this work aims on the synthesis of coumarin compounds analogous to alkylamino-indanone prototypes, described as inhibitors for both AChE enzyme and Aβ plaques aggregation. The disign of the series was based on: 1- the maintenance of the cyclic alkylamino group; 2- in the exchange of the indanone nucleus by the coumarin, through nonclassical isosterism of ring expansion. The synthesis of compounds involved: O-alkylation of 7-hydroxycoumarin; bromination at the 3-position of the 7-bromoalkoxycoumarins; amination of the alkyl chain of 3-bromo-7-bromoalkoxycoumarins; Suzuki coupling reaction of the 3- bromo-7-aminoalkoxycoumarins; Buchwald coupling reaction of the 3-bromo-7-aminoethoxycoumarins; all reactions presented regular to good yields. After purification, the characterization of compounds by spectroscopic techniques (1H and 13C NMR) and high resolution mass spectrometry confirmed the products. All synthesized compounds were able to inhibit AChE selectively against BChE, in which the most active compound presented IC50 = 19 nM and selectivity of 354 (BChE IC50 / AChE IC50), acting very similarly to reference drug donepezil (AChE IC50 = 2 nM and selectivity of 365). Additionally, the compounds showed mixed inhibition profile for both cholinesterases, which was corroborated by molecular docking analyzes that demonstrated the interaction of the compounds with the catalytic (CAS) and peripheral (PAS) sites.

MEMBROS DA BANCA:
Presidente - 1700480 - ARTHUR EUGEN KUMMERLE
Interno - 1220404 - CARLOS MAURICIO RABELLO DE SANTANNA
Externo à Instituição - MARIA LETÍCIA DE CASTRO BARBOSA - UFRJ
Externo à Instituição - MARINA AMARAL ALVES - UFRJ
Interno - 1979542 - RENATA BARBOSA LACERDA