Targeting SIRT2 with Oxadiazole/Thiadiazole-Based Acetamides: In Silico Screening and In Vitro Cytotoxicity Evaluation

As a key member of the human sirtuin family, Sirtuin 2 (SIRT2) is crucial in orchestrating numerous biological processes, such as cell cycle regulation, apoptosis, and metabolic homeostasis, and has emerged as a promising biomarker for various conditions, particularly neurodegenerative diseases, and cancer. Given the growing therapeutic interest focused toward SIRT2 inhibition, we have synthesized a series of 1,3,4-oxadiazole/thiadiazole-2-arylthioacetamides featuring 2-/3-substituted benzyl or pyrimidin-2-ylmethyl at the 5th position of the oxadiazole/thiadiazole ring, to evaluate their potential as SIRT2 inhibitors. Among the compounds synthesized, ST95 displayed selective inhibitory activity against SIRT2 with an IC50 value of 10.62 µM and inhibited the growth of MCF-7 (IC50 = 111.10 µM) and LNCaP (IC50 = 14.69 µM) cancer cell lines, highlighting its potential as a lead compound for further development.