Semi-synthesis and activity study of α-mangostin ether derivatives bearing N-heterocyclic side chains as multitarget-directed ligands against AD

Alzheimer's Disease (AD) is a neurodegenerative disorder with intricate pathogenic factors. Multi-target drug design offers a promising approach to address AD's complex pathogenesis. α-Mangostin (α-M), a natural product with multifunctional anti-AD potential, is limited by poor aqueous solubility and bioavailability. This work employed regioselective Williamson O-alkylation to semi-synthesize three novel α-M alkylamine derivatives (1-3), enabling tunable mono- and disubstitution. In silico predictions demonstrated that disubstituted compounds 2 and 3 exhibited markedly improved blood-brain barrier permeability and oral bioavailability. While, experimental results showed that monosubstitution optimally balanced intrinsic antioxidant activity with target binding properties. Compound 1 displayed potent AChE inhibition (IC₅₀ = 0.11 μM) with high selectivity (SI = 59.27), effectively inhibited both self-induced and AChE-induced Aβ aggregation (53.8% and 57.3%, respectively), and exhibited excellent antioxidant capacity (·OH IC₅₀ = 0.19 μM). Meanwhile, disubstitution achieved superior BuChE inhibition by occupying both sides of the expanded active site pocket. Furthermore, 1 significantly reduced ROS levels by ∼48% in C. elegans. These results highlight the potential of tunable α-M derivatives as promising anti-AD candidates.