Multifunctional phenyl piperidinyl triazoles targeting cholinesterase: toward next-generation Alzheimer’s therapeutics

Abstract Alzheimer’s disease is a progressive neurodegenerative disorder with no disease-modifying therapy. Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) remains a validated strategy for improving cognitive function. Here, nineteen piperidinyl-triazole derivatives ( 9a-9s ) were synthesized, characterized by IR and NMR spectroscopy, and evaluated as dual cholinesterase inhibitors against eserine. Most were active in the micromolar range. Compound 9h was the most effective AChE inhibitor (95.26 ± 1.12% inhibition; IC 50 18.24 ± 0.68 µM) and 9c the most active against BChE (84.51 ± 1.24%; IC 50 82.36 ± 1.15 µM), although both remain considerably less potent than eserine. Electron-donating para substituents on the propionamide-linked phenyl ring enhanced inhibition, whereas electron-withdrawing groups reduced it. Compound 9s was the most effective anti-biofilm agent against Escherichia coli and Staphylococcus aureus , and most derivatives caused negligible hemolysis of bovine erythrocytes, with 9j showing no detectable lysis. Density functional theory indicated stable frontier orbital gaps and favourable reactivity descriptors, and molecular docking placed the compounds within the catalytic and peripheral anionic sites of both enzymes. Predicted physicochemical, CNS-permeability and toxicity profiles were largely favourable. These results identify the piperidinyl-triazole scaffold as a starting point for the development of dual cholinesterase inhibitors.