# Design, Synthesis and Biological Evaluation of Chromeno[3,4‑b]xanthones as Multifunctional Agents for Alzheimer’s Disease

## TL;DR

Researchers designed and tested new compounds that show promise in treating Alzheimer's disease by targeting multiple key factors.

## Contribution

A novel class of chromeno[3,4-b]xanthones is introduced as multifunctional agents for Alzheimer’s disease.

## Key findings

- Compound 11r showed potent inhibition of cholinesterase and significant antiamyloid activity.
- Molecular studies revealed strong binding of compound 11r to Aβ42 fibrils, disrupting amyloid aggregation.
- Compound 11r demonstrated favorable drug properties, including BBB permeability and low efflux from the brain.

## Abstract

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-b]­xanthones as a novel multifunctional scaffold, synthesized via the
straightforward cyclization of their precursor, (E)-2-styrylchromones. Compounds 10 and 11q–s exhibited potent and selective cholinesterase
inhibition (IC50 1.7–9.0 μM for AChE and BChE),
along with significant antiamyloid activity (inhibition exceeding
50% at 50 μM). Among them, compound 11r 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 11r to AChE and BChE. Moreover, docking
and molecular dynamics simulations showed that compound 11r binds strongly to the L-S-shaped β-amyloid 1–42 (Aβ42) fibril with a binding affinity of −11.3 kcal/mol,
representing a structural barrier to Aβ42 elongation.
Additionally, compound 11r, selected as the representative
scaffold, effectively disrupted Aβ aggregation, as demonstrated
by in vitro 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-b]­xanthone as multifunctional agents
for AD, broadening the chemical space of small-molecule exploration.