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

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 <i>ortho</i>-position of R₁ substituent. Selected derivatives also demonstrated low toxicity and protective antioxidant effects in <i>Saccharomyces cerevisiae</i>, significantly reducing lipid peroxidation.