Inhibition of Acetylcholinesterase by Coumarin-Linked Amino Acids Synthetized via Triazole Associated with Molecule Partition Coefficient

Abstract

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.

An Overview of 1,2,3-triazole-Containing Hybrids and Their Potential Anticholinesterase Activities

“…The findings of this study indicated that replacing tyrosol with tyrosine, tryptophan, phenylalanine, and glycine amino acids in the 1,2,3-triazole ring does not improve the anti-AChE spectrum. Conversely, the presence of a carboxylic acid group in 1,2,3-triazole hybrids decreases AChE inhibitory activity [ 104 ].…”

Effects of Coumarinyl Schiff Bases against Phytopathogenic Fungi, the Soil-Beneficial Bacteria and Entomopathogenic Nematodes: Deeper Insight into the Mechanism of Action

“…The AS is responsible for positioning acetylcholine in the enzyme cavity and as a site for possible inhibitor binding. The AP guarantees the specificity of the enzyme to the substrate by preventing the entry of larger molecules into the catalytic site, while PAS portion represents a region that is important for the binding of many inhibitors [ 55 ]. According to Figure 3 b, PAS residues TYR-70, ASP-72, and TYR-334 formed a van der Waals interaction, an attractive charge interaction, and a π–π T-shaped interaction with compound 9 , respectively.…”

“…Additionally, van der Waals interactions were noted between compound 9 and residues ILE-275, ASP-276 and ILE-287. The involvement of the mentioned residues from the AS, AP, and PAS was confirmed to contribute stability to the complex between AChE and synthetic inhibitors such as coumarin-triazole-amino acid hybrids [ 55 ], tyrosol 1,2,3-triazole analogs [ 56 ], coumarin-3-carboxamide-N-morpholine hybrids [ 57 ], chromone derivatives [ 28 ], and chromenyl coumarate [ 58 ].…”

Mucuna pruriens Seed Aqueous Extract Improved Neuroprotective and Acetylcholinesterase Inhibitory Effects Compared with Synthetic L-Dopa

“…Some of these compounds were AChE inhibitors, for example, physostigmine, which can enhance central levels of synaptic choline [ 40 ]. The aromatic amino acids such as tyrosine, phenylalanine, and tryptophan were identified as AChE inhibitors [ 41 ]. Pan et al reported that flavonoid glycoside can inhibit AChE leading to a significant improvement in dyskinesia recovery rate in zebrafish [ 11 ].…”