Síntese de compostos alquilamino-cumarínicos planejados como inibidores da acetilcolinesterase e agregação de placas βamiloides para o tratamento da doença de Alzheimer

Abstract

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 is one 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 design 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 = 0,02 µM and selectivity of 337 (BChE IC50 / AChE IC50), acting very similarly to reference drug donepezil (AChE IC50 = 0,007 µM and selectivity of 341). 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.