Franco_2026_ACS.Omega_11_13184

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 IC(50) values of up to 0.38 microM 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 R(1) and R(2) 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 Cu(2+) and Fe(3+) for the 3-amino-1,2,4-triazole compounds, which could be expanded to other metals by specific structural modifications in ortho-position of R(1) substituent. Selected derivatives also demonstrated low toxicity and protective antioxidant effects in Saccharomyces cerevisiae, significantly reducing lipid peroxidation.