# 4‑Chlorobenzylamine Containing Maleic Acid Derivatives: Synthesis, In Silico Studies, and Anti-Alzheimer’s Activity

## TL;DR

This study explores new maleic acid derivatives that may protect the brain from Alzheimer's-related damage by reducing inflammation and oxidative stress.

## Contribution

The paper introduces novel maleic acid derivatives with promising anti-Alzheimer's and antioxidant properties.

## Key findings

- Compounds 2a and 2f showed strong acetylcholinesterase inhibition and antioxidant activity in vitro.
- In vivo tests showed these compounds reduced oxidative stress and improved cognitive function in rats.
- Molecular docking revealed interactions with key neuroinflammatory targets like COX-2 and TNF-α.

## Abstract

One way to protect neurons is to protect them from oxidative
damage
by reducing lipid peroxidation (LPO). Therapeutic medicines that target
the inflammatory response have antioxidant activities and can also
block inflammatory cascade pathways and counteract cell lyses. The
goal of this investigation was to see if new maleic acid derivatives
could protect the brain from scopolamine-induced amnesia. To evaluate
and characterize the maleic acid derivatives, spectroscopic techniques
such as 1H NMR and Fourier Transform Infrared Spectroscopy
(FTIR) were used. To further evaluate the synthesized compounds, an
in vitro DPPH antioxidant assay was performed, compound 2f exhibited
the best antioxidant potential, and along this side, an acetylcholinesterase
(ACE) inhibition assay was performed. Compounds 2a and 2f showed promising
results with IC50 20.15 and 22.09 nM, respectively. Scopolamine-treated
rats trigger neurodegeneration, raise the level of antioxidant enzymes,
and increase oxidative stress. The elevated levels of Tumor Necrosis
Factor α (TNF-α), cyclooxygenase-2 (COX-2), Jun N-terminal
kinase (JNK), and Nuclear Factor kappa-light-chain-enhancer of activated
B cells (NFκB), which are neuroinflammatory mediators, along
with neuronal damage, were also seen. The anti-Alzheimer’s
activity of maleic acid derivatives was performed in these rats by
performing the Y-maze test, Morris water maze (MWM) models, immunohistochemistry,
and hematoxylin and eosin staining. In vivo antioxidant assays revealed
that compounds 2a and 2f significantly restored enzymatic defenses
and reduced lipid peroxidation, with 2a showing slightly superior
activity. The maleic acid derivatives (2a and 2f) cause increased
spontaneous changes in the rat behavior and the number of entries
of rats in the Y-maze test. The observation from the MWM model showed
a decrease in the escape latency time in the rats. Finally, the AutoDock
Vina program was used to check ligand-protein interaction using COX-2,
and TNF-α, JNK, NFκB, GSK-3β, and ACE were used
as targets.