Discovery of SIRT1-Activating Hydrogen Sulfide Donating Derivatives for Efficient Resistant of Myocardial Ischemic Injury

Activating SIRT1 or promoting SIRT1 expression are both protective against myocardial ischemia. Combining these approaches would be an effective strategy for treating ischemic heart disease. Herein, we identified lead compounds with SIRT1 activation activity through screening the natural product library, and five series of H₂S donating derivatives were designed and synthesized. Among them, compound <b>17</b> exerted an effective cardioprotective effect <i>in vitro</i> and <i>in vivo</i>. The addition of H₂S scavenger attenuated the protective activity, emphasizing the critical involvement of H₂S in the myocardial ischemia process. Interestingly, <b>17</b> exhibited stronger direct SIRT1 activative ability and induced higher SIRT1 expression capability compared to the lead. Furthermore, <b>17</b> attenuates oxidative stress-induced cardiomyocytes apoptosis by activating the SIRT1-PGC1α signaling pathway. Our study validated the promising potential of activating SIRT1 and promoting SIRT1 expression through H₂S to improve cardiomyocytes function, providing novel insights into the protective mechanisms during the progression of ischemic heart disease.