Alzheimer's disease (AD) is the most common type of dementia and related to the degeneration of hippocampal cholinergic neurons, which dramatically affects cognitive ability. Acetylcholinesterase (AChE) inhibitors are employed as drugs for AD therapy. Three series of sulfonylhydrazone compounds were designed, and their ability to inhibit AChE was evaluated. Fifteen compounds were synthesized and twelve of them had IC values of 0.64-51.09 μM. The preliminary structure-activity relationships indicated that the methylcatechol moiety and arylsulfonyl substituents generated better compounds than both the benzodioxole and alkylsulfonyl chains. Molecular dynamics studies of compound 6d showed that the interaction with the peripheral binding site of AChE was similar to donepezil, which may explain its low IC (0.64 μM). Furthermore, the drug-likeness of 6d suggests that the compound may have appropriate oral absorption and brain penetration. Compound 6d also presented antiradical activity and was not cytotoxic to LL24 cells, suggesting that this compound might be considered safe. Our findings indicate that arylsulfonylhydrazones may be a promising scaffold for the design of new drug candidates for the treatment of AD.
Background:
The most important cause of dementia affecting elderly people is the Alzheimer’s
disease (AD). Patients affected by this progressive and neurodegenerative disease have
severe memory and cognitive function impairments. Some medicines used for treating this disease
in the early stages are based on inhibition of acetylcholinesterase. Population aging should
contribute to increase the cases of patients suffering from Alzheimer's disease, thus requiring the
development of new therapeutic entities for the treatment of this disease.
Methods:
The objective of this work is to identify new substances that have spatial structural
similarity with donepezil, an efficient commercial drug used for the treatment of Alzheimer's
disease, and to evaluate the capacity of inhibition of these new substances against the enzyme
acetylcholinesterase.
Results:
Based on a previous results of our group, we prepared a set of 11 spirocyclohexadienones
with different substitutions patterns in three steps and overall yield of up to 59%. These
compounds were evaluated in vitro against acetylcholinesterase. We found that eight of them are
able to inhibit the acetylcholinesterase activity, with IC50 values ranging from 0.12 to 12.67 µM.
Molecular docking study indicated that the spirocyclohexadienone, 9e (IC50 = 0.12 µM), a mixedtype
AChE inhibitor, showed a good interaction at active site of the enzyme, including the cationic
(CAS) and the peripheral site (PAS).
Conclusion:
We described the first study aimed at investigating the biological properties of spirocyclohexadienones
as acetylcholinesterase inhibitors. Thus, we have identified an inhibitor, which
provided valuable insights for further studies aimed at the discovery of more potent acetylcholinesterase
inhibitors.
A β-secretase (BACE-1) é uma enzima que hidrolisa a proteína precursora do amiloide (PPA), dando origem a oligopeptídeos. Estes apresentam propriedades auto-agregantes, levando à formação de oligômeros tóxicos e às placas amiloides. Este processo de clivagem da PPA, conhecido como via amiloidogênica, é uma importante característica da doença de Alzheimer (DA). O projeto dedica-se à síntese e caracterização de chalconas derivadas da 2'aminoacetofenona, com diferentes padrões de substituição no anel A (Figura 1), para estudar o seu efeito inibitório sob atividade da β-secretase.
melhor educação e treinamento disponíveis, mantenha sua percepção elevada, seja persistente, seja flexível, mantenha suas opções abertas, aceite ajuda quando oferecida e esteja preparado para ajudar os outros." Mildred Dresselhaus Agradecimentos Agradeço a Deus pela oportunidade de aprender sempre. Aos meus pais João e Arléte por sempre me apoiarem em conquistar meus sonhos. Ao meu esposo e companheiro Denis pela paciência nos momentos difíceis. A minha família por me apoiar sempre: minha irmã Denise, minhas tias Célia e Margareti, minha vó Concheta, meu vô João e minha vó Bel (in memoriam), minhas primas Maini e Monique, minha sogra Elza e minha cunhada Thais. Agradeço às crianças da família pelos momentos de alegria: Pedro Henrique, Glorinha, Larissa e Isabeli. A Professora Wanda Pereira Almeida, pela oportunidade de fazer parte do grupo Laboratório de Fármacos e Medicamentos (LAFAME). Agradeço imensamente pela orientação e amizade.
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