Discovery of\nSIRT1-Activating Hydrogen Sulfide Donating\nDerivatives for Efficient Resistant of Myocardial Ischemic Injury

Activating SIRT1 or promoting SIRT1 expression are both\nprotective\nagainst myocardial ischemia. Combining these approaches would be an\neffective strategy for treating ischemic heart disease. Herein, we\nidentified lead compounds with SIRT1 activation activity through screening\nthe natural product library, and five series of H<sub>2</sub>S donating\nderivatives were designed and synthesized. Among them, compound <b>17</b> exerted an effective cardioprotective effect <i>in\nvitro</i> and <i>in vivo</i>. The addition of H<sub>2</sub>S scavenger attenuated the protective activity, emphasizing\nthe critical involvement of H<sub>2</sub>S in the myocardial ischemia\nprocess. Interestingly, <b>17</b> exhibited stronger direct\nSIRT1 activative ability and induced higher SIRT1 expression capability\ncompared to the lead. Furthermore, <b>17</b> attenuates oxidative\nstress-induced cardiomyocytes apoptosis by activating the SIRT1-PGC1α\nsignaling pathway. Our study validated the promising potential of\nactivating SIRT1 and promoting SIRT1 expression through H<sub>2</sub>S to improve cardiomyocytes function, providing novel insights into\nthe protective mechanisms during the progression of ischemic heart\ndisease.