Síntese e avaliação farmacológica de novos 3-amino-1,2,4-triazóis como inibidores de enzimas envolvidas na doença de Alzheimer

Abstract

Alzheimer's DIsease is a chronic neurodegenerative disorder, capable of provoking progressive loss of memory and other functions. It is a complex disease, multifactorial and with an unknown origin. Characterized by decrease of cholinergic neuronal activity; deposition of anomalous protein aggregates; neuroinflammation; disfunction of metallic homeostasis; and oxidative stress. Currently, the treatment is based on symptomatic control, mainly with cholinesterase inhibitors. Due the unsuccessful clinical results of most of the drug been being very relevant in this context. Therefore, the objective of this paper is synthesis and pharmacological evaluation of a hybrid series of 1,3-amino-1,2,4-triazoles as multitarget for -classic isosteric exchange of triazines for 3-amino-1,2,4-triazoles; and molecular hybridization with the classic drug donepezil. The compounds containing 1,3-amino-1,2,4-triazoles nucleus were obtained through the regioselective synthesis from N-acyl-2-methyl-isothiourea N-Boc using microwave irradiation (Y= 45% - 88%). Followed by alkylation reactions (37% - 79%); amination (35% - 66%); and deprotection of Boc group (85% - 96%), obtaining the final products, which were characterized by RMN 1H and 13C. The amino-1,2,4-triazoles carrier R1= NO2 (AChE; IC50 = 0,386; IS= 5,86) and R1= Bz (BChE; IC50 = 0,416, IS= 3,66) presented the highest inhibitory activities to the cholinesterases AChE and BuChE respectively, in addition, presented mixed inhibition profile in the assays of enzymatic kinetics. Furthermore, the molecular docking has showed the mainly interactions between the 1,3-amino-1,2,4-triazoles with the residue W86, W286 and Y124 of AChE active site. However, the 1,3-amino-1,2,4-triazoles have not showed antioxidant activities in DPPH assay. In the end, spectroscopic results of fluorescent emission indicate the formation of the triazole complex containing R1: H; R1: 2-OH; e R1: 2-piridine with metallic ions, Zn2+, Cu2+, Al3+, Fe3+. The results were promising, because were obtained more active compounds than the prototype, including the capacity of complexing with metallic ions, important properties to defeat Alzheimer. As a perspective, the series of amino-1,2,4-triazoles will be send to assays of βA aggregation inhibition and neurotoxicity; and the exploration of new series varying substituents in benzylpiperazine group.