Synthesis and evaluation of 1,4-disubstituted 1,2,3-triazole derivatives with multi-target activity in Alzheimer's disease

Alzheimer's disease (AD) is characterized by deposition of insoluble tau and β-amyloid protein fragments, neuroinflammation and oxidative stress in the brain, leading to neuronal death and consequent cholinergic deficit. It is a progressive, debilitating and incurable disease with a very restricted therapeutic arsenal. In this context, the search for new substances that can improve the therapeutic proposals for AD is crucial. This study aimed the synthesis and pharmacological evaluation of a new family of compounds designed from the molecular hybridization of known bioactive natural products. Thirteen molecules were prepared and evaluated for AChE inhibition, antioxidant and neuroprotective capacity and had their toxicological aspects determined. Compound PQM-233 was identified as the most promising hybrid ligand with IC50=20.22 µM for AChE inhibition, IC50=30.44 µM in DPPH assay, inhibitory activity of ROS formation in neuronal cells and neuroprotective activity against neurotoxicity induced by β-amyloid oligomers. In addition to these properties, PQM-233 showed no significant toxicity in any of the pharmacologic models.