Open AccessInhibition of Acetylcholinesterase by Coumarin-Linked Amino Acids Synthetized via Triazole Associated with Molecule Partition Coefficient
Author(s) -
Bianca Lana de Sousa,
João Paulo Viana Leite,
Tiago Antônio de Oliveira Mendes,
Eduardo Vinícius Vieira Varejão,
Anna C. S. Chaves,
Júnio G. da Silva,
Ana Paula Agrizzi,
Patrícia Rodrigues Ferreira,
Eduardo Jorge Pilau,
Evandro Silva,
Marcelo Henrique dos Santos
Publication year - 2021
Publication title -
journal of the brazilian chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.337
H-Index - 70
eISSN - 1678-4790
pISSN - 0103-5053
DOI - 10.21577/0103-5053.20200219
Subject(s) - chemistry , coumarin , triazole , stereochemistry , 1,2,3 triazole , acetylcholinesterase , moiety , glycine , amino acid , enzyme , molecule , organic chemistry , biochemistry
A previous study for the identification of acetylcholinesterase (AChE) inhibitors demonstrated that the hybrid between tyrosol, the 1,2,3-triazole nucleus, and the coumarin group, namely 7-({1-[2-(4-hydroxyphenyl)ethyl]-1H-1,2,3-triazol-4-yl}methoxy)-4-methyl-2H-chromen-2-one (10), has a high enzyme inhibitory activity. Here, we synthesized analogues of 10 via triazole with pharmacophoric groups represented by tyrosine, phenylalanine, tryptophan, and glycine in addition to evaluating the impact of coumarin-linked amino acids on AChE inhibition. We obtained eight triazoles, six of which are undescribed. In general, the presence of carboxylic acid decreased the inhibitory activity, while aromatic amino acids increased enzymatic inhibition compared to glycine. The derivative containing tyrosine, structurally most similar to 10, presented the lowest inhibition percentage, indicating that phenolic hydroxyl is not the preponderant factor for inhibition. Molecular docking was not enough to explain in vitro experiments. On the other hand, MlogP (logP calculated by the Moriguchi method) was related positively to enzymatic inhibition. To increase the hydrophobicity of the molecules, we tested the esterified triazole derivatives comparatively with the enzyme. The compound ethyl 2-(4-(((4-methyl-2-oxo-2H-chromen-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)acetate (6) presented an increment of inhibitory activity of 46.97 ± 1.75% at 100 μmol L-1. We also associated the best activity with the lowest van der Waals volume and molar mass values.