Síntese e avaliação farmacológica de novas 3-(1,2,3-triazol)-cumarinas planejadas para o tratamento da Doença de Alzheimer

Abstract

Alzheimer’s Disease (AD) is a progressive and irreversible neurodegenerative disorder, which affects memory and other cognitive functions, also affecting ocupational and social aspects. Using hybrid compounds with inhibition potential to multiple targets, like acetylcholinesterase enzyme (AChE) and β-amyloid peptides plaques aggregation (Aβ), has been observed as a high value objective for AD treatment due to possibilty to inhibit simultaneously different targets that contribute to instalation and maintenance of the disease. AChE acts controlling levels of the neurotransmitter acetylcholine (ACh) in synaptic cleft, that plays a role in the processes of learning and memory developing. The aggregation of Aβ plaques is one of the main responsible for neuronal death. Recent published studies by our research group (LaDMol-QM) revealed the alkylamino-coumarin nucleus as a potential inhibitor of AChE and Aβ plaques aggregation. These results inspired a planned developing serie of new 3-(1,2,3-triazole)-coumarin derivatives purposed in this paper, based in structural aspects existent in those alkylamino-coumarin inhibitors, where it was purposed an evaluation of different cyclic alkylamino groups, also the evaluation of different sizes of alkyl chain between the alkylamino group and coumarin group, the addition of 1,2,3-triazole group with different substituents. The compounds were synthesized in yields reasonable to good from reactions of: synthesis of 7-hydroxycoumarin, O-alkylation of 7-hydroxycoumarin with a dibromides serie with different chain sizes, bromation of position 3 of coumarin nucleus of the 7-bromoalkoxy-coumarin, reaction of Sonogashira’s cross-coupling from 3-bromo-7-bromoalkoxy-coumarin, deprotection of trimethylsilyl group of 7-bromoalkoxy-3-((trimethylsilyl)ethenyl)-coumarin, reaction of 1,3-dipolar cycloaddition copper catalyzed (CuAAC), using 3-ethenyl-7-bromo-alkoxy-coumarin and aromatic azides, amination of alkyl chain of 3-(1H-1,2,3-triazol-4,R1)-7-(aminoalkoxy)-coumarin. The compounds were purified and then characterized by spectroscopic techniques (NMR 1H e 13C). As a result, all synthesized compounds were able to inhibit AChE, based on assays and presented IC50 values from 0,006 to 4,79 μM.