Design, Synthesis, and Protective Effect Evaluation on Myocardial Ischemia of New Triazole Aldehyde Dehydrogenase 2 Activators

Myocardial infarction (MI) is a serious human health problem, with high mortality and unfavorable prognosis. In this study, new triazole aldehyde dehydrogenase 2 (ALDH2) activators with improved water solubility and activity were discovered with the aid of molecular simulation. The ALDH2 maximum activation fold of representative compound Z17 reached 5.4, which is 304% calibrated against the positive control Alda-1. This activation activity represents the highest activity among the compounds which have been reported so far to our knowledge. This compound exhibited significant efficacy not only in enhancing cardiac function (improved cardiac ejection fraction by 41% and fractional shortening by 36%) but also in mitigating myocardial necrosis (improved the size of myocardial infarction by 38%, levels of LDH by 35% and CK-MB by 69%) in a mice model of myocardial ischemia-reperfusion via intraperitoneal injection. This study provides a good basis for further research on ALDH2 activators to treat MI.