Modular Biomimetic Strategy toward Discovery of Macrocyclic Sulfonamides as SIRT3 Activators against Heart Failure

Abstract Heart failure (HF) remains a severe global cardiovascular disease with limited targeted therapies. Mitochondrial deacetylase SIRT3 is a promising therapeutic target for HF, yet current SIRT3 agonists suffer from low potency and poor isoform selectivity. Herein, we adopted a modular biomimetic strategy to synthesize a series of macrocyclic sulfonamides and systematically explored their structure-activity relationships. The lead compound 2b (Y0855) exhibited potent SIRT3 agonistic activity (EC50 = 12.6 μM, and Emax = 4.05) and excellent selectivity over SIRT1/2/6. Mechanistically, 2b alleviated cardiomyocyte oxidative stress, cell injury and fibrosis via SIRT3 activation. In a doxorubicin-induced HF mouse model, it markedly restored cardiac function and mitigated myocardial damage. Moreover, 2b possessed improved metabolic stability, making it a valuable lead compound for anti-HF drug development targeting SIRT3.