Design, synthesis, and biological evaluation of new ALDH2 activators

Abstract EN

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is an important enzyme response for the metabolism or detoxification of toxic aldehydes, in particular acetaldehyde and 4-hydroxynonenal (4-HNE), which were important risk factors for acute alcoholism and stroke respectively.

A special variant ALDH2*2 with reduced enzymatic activity was carried by a high percentage of East Asians, especially Han Chinese, and that could increase the risk of these diseases further.

Therefore, ALDH2 activators had important potential clinical values.

N-benzylbenzamide compounds represented by Alda-1 were the only ALDH2-specific activators that have been reported so far.

In this study, three new classes of compounds were modified from Alda-1 to improve their water-solubility and then drug-like properties.

The results showed that all compounds had increased water solubility and two classes of compounds exhibited good activation activity.

Among them, compound I-6 showed the best activity.