# Novel cinnamic acid-based N-benzyl pyridinium analogs: potent dual cholinesterase inhibitors with neuroprotective properties for Alzheimer's disease

## TL;DR

This study develops new compounds that effectively inhibit enzymes linked to Alzheimer's and protect brain cells from damage.

## Contribution

The paper introduces novel cinnamic acid-based compounds with dual cholinesterase inhibition and neuroprotective properties.

## Key findings

- Compound 7b showed strong inhibition of AChE and BChE with IC50 values of 0.89 µM and 0.11 µM, respectively.
- Compound 7b exhibited significant neuroprotection in SH-SY5Y cells without cytotoxicity.
- Molecular docking and simulations confirmed stable binding interactions in enzyme active sites.

## Abstract

This study reports the design and synthesis of a novel series of cinnamic acid-based analogs bearing an N-benzyl pyridinium moiety against Alzheimer's disease (AD), aiming at dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), alongside neuroprotective effects. A total of 15 derivatives were synthesized, among which compound 7b exhibited the most potent dual inhibition (AChE IC50 = 0.89 µM; BChE IC50 = 0.11 µM), and significant neuroprotection against H2O2-induced oxidative stress in SH-SY5Y cells, with no cytotoxicity under the tested concentration. Structure–activity relationship (SAR) analysis revealed that small electron-withdrawing substituents (e.g. ortho-fluoro, methyl) enhanced inhibitory activity, whereas meta and para substitutions generally reduced potency. Enzyme kinetics also determined compound 7b to be a competitive inhibitor of AChE (Ki = 0.49 µM). Furthermore, molecular docking and molecular dynamics simulations identified stable binding interactions in the active sites of AChE and BChE. All these findings support the potential of these compounds as effective multi-target-directed ligands (MTDLs) for AD, displaying coordinated inhibition of cholinesterase, neuroprotection, and low toxicity.

This study reports the design and synthesis of cinnamic acid-based analogs bearing an N-benzyl pyridinium moiety against Alzheimer's disease.