Design, Synthesis, and Biological Evaluation of Pyrazolyl Thioureas (PTUs) as SIRT1 and SIRT2 Inhibitors.

A series of pyrazolyl-thioureas was designed and synthesized as novel sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) inhibitors. Compounds were prepared through a multistep, divergent procedure starting from amino pyrazole intermediates. Biological evaluation revealed that several derivatives exhibited significant SIRT2 inhibitory activity, with compounds 6a and 7f emerging as the most promising inhibitors, showing IC50 values of 2.2 and 13.6 µM, respectively. Selected compounds displayed selective antiproliferative activity against HepG2 hepatocellular carcinoma cells, while showing limited cytotoxicity toward normal fibroblasts. The biological properties of 6a and 7f were further investigated by analyzing SIRT1 activity and correlating antiproliferative activity with tubulin acetylation. Docking simulations identified the molecular basis of SIRT1 and SIRT2 inhibition. Overall, these results identify pyrazolyl thioureas as a promising scaffold for novel SIRT1 and SIRT2 inhibitors with potential anticancer applications.