Design, synthesis, biological evaluation, and X-ray single crystal structure of novel computer-aided-drug-designbased α-mangostin derivatives: Multifunctional ligands against Alzheimer's disease.

Multifunctional ligand design strategy may be a promising approach for the treatment of Alzheimer's disease (AD). α-Mangostin (α-M), a natural small molecule with anti-AD properties, was used as the lead compound for the design and synthesis of six α-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-β (Aβ) 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 = 0.016 µM, 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 Aβ 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 α-M showed the best activities and were expected to become promising candidate drugs for multifunctional anti-AD.