# Design, Synthesis, and Study of Protective Activity Against Stroke for Novel Water-Soluble Aldehyde Dehydrogenase 2 Activators

## TL;DR

Researchers developed new water-soluble compounds that activate ALDH2, which may help treat stroke by reducing brain damage in animal models.

## Contribution

The study introduces novel water-soluble ALDH2 activators with significantly improved solubility and efficacy for stroke treatment.

## Key findings

- Compound D10 showed 114% activation of ALDH2 compared to Alda-1.
- The hydrochloride salt D27 had over 200-fold increased water solubility.
- Intravenous D27 reduced infarct area in rat stroke models.

## Abstract

Stroke poses a serious threat to human health, while there are very few drugs that can directly alleviate ischemia/reperfusion injury and improve the prognosis. Studies have shown that small-molecule activators of aldehyde dehydrogenase 2 (ALDH2) have the potential to become novel therapeutic drugs for ischemic stroke. In this study, through the systematic structural optimization of novel N-benzylaniline-based ALDH2 activators obtained from our previous virtual screening, ALDH2 activators with improved water solubility and activity were obtained. Among them, compound D10 exhibits the best activity, with a maximum activation fold reaching 114% relative to Alda-1. And the water solubility of its hydrochloride salt D27 was increased by more than 200-fold. The intravenous injection of this compound can significantly reduce the infarct area in the rat model of cerebral infarction compared with the model group. This study lays a good foundation for the future research on ALDH2 activators used in the treatment of stroke.