Design, synthesis, and biological evaluation of new ALDH2 activators

• Main Authors: Jian Hu, Wei Tian, Ruolan Zhou, Yuefan Zhang, Jiaguo Lv, Ju Zhu, Xin Chen, Xianhua Pan, Canhui Zheng
• Format: Article
• Language: English
• Published: Elsevier 2019-03-01
• Series: Journal of Saudi Chemical Society
• Online Access: http://www.sciencedirect.com/science/article/pii/S1319610318300814

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. Keywords: Mitochondrial aldehyde dehydrogenase 2, Activators, Synthesis, Biological evaluation