Chen_2025_Arch.Pharm.(Weinheim)_358_e2400671

Multifunctional ligand design strategy may be a promising approach for the treatment of Alzheimer's disease (AD). alpha-Mangostin (alpha-M), a natural small molecule with anti-AD properties, was used as the lead compound for the design and synthesis of six alpha-M derivatives (1-6) with the help of computer-aided-drug-design (CADD). Both theoretical calculations and experimental results suggested that 1-6 might serve as promising selective butyrylcholinesterase (BuChE) inhibitors and amyloid-beta (Abeta) aggregation inhibitors. Meanwhile, experimental results confirmed the high selectivity of the derivatives, in which 1 had the best inhibitory activity and selectivity on BuChE (IC(50) = 0.016 microM, SI = 700.63). The experimental results also showed that 1-6 could act as copper chelators and reactive oxygen species (ROS) scavengers. Furthermore, in vivo experiments with Caenorhabditis elegans also showed that 1 could scavenge ROS and inhibit Abeta aggregation. Notably, single crystals of 1, 4, and the 4-Cu(II) complex were prepared for the first time, which provided a reliable structural basis for analyzing the structure-activity relationship. The dimethylamino derivatives (1, 4) of alpha-M showed the best activities and were expected to become promising candidate drugs for multifunctional anti-AD.