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

Authors

Matteo Lusardi, Cecilia Astigiano, Deianira Bellitto, Matteo Raineri, Giorgia Guccione, Annalisa Salis, Elena Cichero, Chiara Brullo, Marco Ponassi, Santina Bruzzone, Andrea Spallarossa

Published in

ChemMedChem. Volume 21. Issue 18. Pages e70489. Sep 28, 2026.

Abstract

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.

PMID:
42778514
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.

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