# Novel Benzofuran-3-yl-methyl and Aliphatic Azacyclics: Design, Synthesis, and In Vitro and In Silico anti-Alzheimer Disease Activity Studies

## TL;DR

This study designs and tests new compounds that may help treat Alzheimer's disease by inhibiting key enzymes linked to the condition.

## Contribution

The paper introduces novel benzofuran-azacyclic hybrids with dual inhibitory activity against AChE and BACE-1 enzymes.

## Key findings

- Compound 4m showed the highest inhibitory potency by effectively occupying AChE and BACE-1 enzyme sites.
- Compounds 4e and 4h exhibited dual inhibitory activity on both AChE and BACE-1 enzymes.
- The tubular form with a stopper group is proposed as a potential pharmacophore for Alzheimer's drug development.

## Abstract

Neurological disorders represent a significant burden
on human
health, particularly as global life expectancy continues to rise.
Among these conditions, Alzheimer’s disease is notably prevalent.
Of greater concern, if left untreated or unaddressed, Alzheimer’s
disease can progress to dementia, leading to severe cognitive decline
and a substantial reduction in quality of life. In this study, 15
novel benzofuran-azacyclic hybrids were designed and synthesized.
The final compounds were evaluated for their inhibitory potency on
AChE and BACE-1 enzymes, and in silico studies were performed to clarify
their binding modes. Finally, structure–activity relationships
(SARs) were proposed for future studies. The results indicated that
the most promising compound is 4m, which contains N-(2-hydroxyethyl)­piperazine and benzofuran moieties. These
moieties effectively occupied the substrate channel of the AChE enzyme
and the catalytic cleft of the BACE-1 enzyme. Additionally, compounds 4e (benzyl piperidine) and 4h (2-furoyl piperazine)
showed dual inhibitory activity on both enzymes. In conclusion, the
tubular form with a stopper group shows great potential for the treatment
of Alzheimer’s disease, as it blocks the entrance cavity of
the AChE active pocket for the substrate and increases the stability
of the inactive BACE-1 enzyme. Moreover, electrolytes, specifically
sodium ions in this case, play a crucial role in stabilizing the 4m-BACE-1 protein complex. For further studies, we suggest
that the tubular form with a stopper can serve as a potential pharmacophore
and an appropriate starting point for drug development.