Design, Synthesis, and Biological Evaluation of Novel Acetylcholinesterase and β-Secretase 1 Inhibitors.

A series of novel granatane-triazole hybrid molecules was designed, synthesized, and evaluated as dual acetylcholinesterase (AChE) and β-secretase 1 (BACE1) inhibitors. The compounds were obtained through a convergent synthetic route involving azide formation, triazole construction via dipolar cycloaddition, and final coupling with a granatane scaffold to give a pseudopelletierine (3-granatanone) analogue. In vitro assays demonstrated that all target compounds inhibited both AChE and BACE1. Molecular docking and molecular dynamics simulations revealed stable interactions with key catalytic residues, suggesting distinct binding modes compared to reference ligands. QSAR-based pharmacokinetic predictions indicated favorable blood-brain barrier permeability and compliance with key drug-likeness filters. These findings identify granatane-triazole hybrids as promising multi-target directed ligand (MTDL) candidates with potential for further optimization in the search for new anti-Alzheimer therapeutics.