Banca de DEFESA: NATHALIA FONSECA NADUR

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
DISCENTE : NATHALIA FONSECA NADUR
DATA : 05/02/2020
HORA: 10:00
LOCAL: PQ sala 50
TÍTULO:

Synthesis and Pharmacological Evaluation of New 3-(1,2,3-triazole)-coumarines Designed for the Treatment of Alzheimer's Disease

PALAVRAS-CHAVES:

Alzheimer, coumarins, cholinesterase inhibitors, beta-amyloid aggregation inhibitors

PÁGINAS: 174
GRANDE ÁREA: Ciências Exatas e da Terra
ÁREA: Química
SUBÁREA: Química Orgânica
ESPECIALIDADE: Síntese Orgânica
RESUMO:

Alzheimer's disease (AD) is characterized as a progressive and irreversible neurodegenerative disorder of memory and other cognitive functions, affecting occupational and social functioning. The use of hybrid compounds with potential inhibitor for more than one target, such as the enzyme acetylcholinesterase (AChE) and the aggregation of β-Amyloid plaques (Aβ), has been shown to be of great value for the treatment of AD due to the possibility of inhibiting AD. simultaneously targets that contribute to the onset and maintenance of the disease. AChE acts to control the levels of the neurotransmitter acetylcholine (ACh) in the synaptic cleft, which is involved in learning and memory processes. Aggregation of Aβ plaques is a major cause of neuronal death. Recent studies have demonstrated the alkyamino-indanone nucleus (19; 20) as a potential inhibitor of AChE enzyme and Aβ plaque aggregation with IC50 values of 14.8 and 16.5nM inhibition against AChE and percentages of inhibition of AChE aggregation. Aβ plates of 85.5% and 83.3% at 20µM, respectively. These results inspired the planned series of new 3- (1,2,3-triazole) coumarin derivatives (21) proposed in this work, based on the structural requirements of these alkylamino-indanone inhibitors, where the maintenance of the alkylamino group was proposed. cyclic, the exchange of indanone by coumarin nucleus, through non-classical ring expansion isosterism and addition of 1,2,3-triazole group. The synthesis of compounds (21a-k) begins by the synthesis of 7-hydroxycoumarin (24) by a Pechmann condensation in 70% yield. Subsequently, an O-alkylation reaction (26a-d) was performed with a series of dibromers with different chain sizes, yielding 46-71%. Subsequently, bromination of position 3 of the coumarin nucleus (28a-d) was carried out via bromination reaction, with yields between 77 and 88%. In the next step, the Sonogashira cross coupling reaction (30a-d) was performed, yielding between 38 and 54%. Subsequently, the alkyne formed was subjected to a deprotection reaction (31a-d) with yields between 76 and 94%. At the same time, azides (33) were synthesized by the diazotation reaction between aromatic amines and sodium azide. Then a reaction of Click Chemistry (34a-d) was then performed between alkynes (31a-d) and azides (33), leading to the formation of the 1,2,3-triazole heterocycle, with yields between 61 and 79%. Finally, an amination reaction was performed on the alkyl chain (21a-k), leading to the final compounds with yield ranging from 52 to 86%. The obtained compounds were purified and then characterized by spectroscopic techniques (1 H and 13 C NMR). All synthesized compounds were able to inhibit AChE, tested and had IC50 values ranging from 0.006 to 4.79 μM.

MEMBROS DA BANCA:
Presidente - 1700480 - ARTHUR EUGEN KUMMERLE
Interno - 1735975 - CEDRIC STEPHAN GRAEBIN
Interna - 1979542 - RENATA BARBOSA LACERDA
Externo à Instituição - DAVID RODRIGUES DA ROCHA - UFF
Externo à Instituição - LEANDRO SOTER DE MARIZ E MIRANDA - UFRJ