Design, Synthesis and Biological Evaluation of Chromeno[3,4-]xanthones as Multifunctional Agents for Alzheimer's Disease.

Alzheimer's disease (AD) remains a complex and unmet medical challenge, requiring innovative approaches to address its multifaceted pathology. In this study, we explored chromeno[3,4-]xanthones as a novel multifunctional scaffold, synthesized via the straightforward cyclization of their precursor, ()-2-styrylchromones. Compounds and - exhibited potent and selective cholinesterase inhibition (IC 1.7-9.0 μM for AChE and BChE), along with significant antiamyloid activity (inhibition exceeding 50% at 50 μM). Among them, compound demonstrated the most well-balanced multifunctional profile against all four AD-relevant targets. Molecular docking studies revealed key π-stacking, hydrogen bonding, and halogen interactions, which underlie the selective binding of compound to AChE and BChE. Moreover, docking and molecular dynamics simulations showed that compound binds strongly to the L-S-shaped β-amyloid 1-42 (Aβ) fibril with a binding affinity of -11.3 kcal/mol, representing a structural barrier to Aβ elongation. Additionally, compound , selected as the representative scaffold, effectively disrupted Aβ aggregation, as demonstrated by studies, transmission electron microscopy (TEM), and cellular studies. It also displayed favorable drug-like properties, including predicted blood-brain barrier (BBB) permeability and an acceptable safety profile at active doses. The calcein-AM-assay also showed that this compound is unlikely to be actively effluxed from the brain. These findings underscore the therapeutic potential of chromeno[3,4-]xanthone as multifunctional agents for AD, broadening the chemical space of small-molecule exploration.