# Synthesis and Pharmacological Evaluation of Novel 1,5-Disubstituted-3-amino-1,2,4-triazoles Designed as Multitarget Directed Ligands for Alzheimer’s Disease Targets

## TL;DR

This paper presents new triazole compounds that show promise for Alzheimer's treatment by targeting multiple disease-related enzymes and metals.

## Contribution

The study introduces novel multitarget-directed 1,2,4-triazole ligands with potent acetylcholinesterase inhibition and metal-binding properties.

## Key findings

- Compounds showed potent acetylcholinesterase inhibition with IC50 values as low as 0.38 μM.
- Molecular dynamics suggested synergistic interactions at key enzyme sites.
- Selected derivatives exhibited antioxidant effects and low toxicity in yeast.

## Abstract

A series of 3-amino-1,2,4-triazole
derivatives was synthesized
and evaluated for their multitarget activities relevant to Alzheimer’s
disease. Inhibition assays revealed potent and preferential inhibition
of acetylcholinesterase (AChE) for most of compounds, with IC50 values of up to 0.38 μM and selectivity ratios up
to 32-fold over butyrylcholinesterase (BChE). Qualitative molecular
dynamics indicated that interactions at the PAS and CAS appear to
occur synergistically, with positive cooperativity. Electron-withdrawing
groups in R1 and R2 favorize PAS interactions
that seem to guide efficient CAS interactions, mainly with residue
Trp86 in AChE and Trp107 in BChE. Metal-binding studies showed intrinsic
complexation of Cu2+ and Fe3+ for the 3-amino-1,2,4-triazole
compounds, which could be expanded to other metals by specific structural
modifications in ortho-position of R1 substituent.
Selected derivatives also demonstrated low toxicity and protective
antioxidant effects in Saccharomyces cerevisiae, significantly reducing lipid peroxidation.