Modular Biomimetic Strategy toward Discovery of Macrocyclic Sulfonamides as SIRT3 Activators against Heart Failure
Xiaoxiao Yang, Simin Liu, Yunxia Cui, Hepeng Liu, Xiaolong Ma, Zhongliang Xu, Tongyu Bi, Xiaojun Xu, Jian Zhang, Weibo YangAbstract
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.