Design, synthesis and anti-cervical cancer activity of aroylpyrrole-based derivatives as potent histone deacetylase 6 inhibitors.

Cancers, such as cervical carcinoma, are one of the most significant diseases affecting human health and histone deacetylases (HDACs) are striking targets in current antitumor drug development. Compared to pan-HDAC inhibitors with potential toxicity, the development of selective HDAC6 inhibitors (sHDAC6is) is a major research focus. In this study, a series of derivatives bearing an aroylpyrrole core were designed and synthesized using a scaffold-hopping strategy. Among these, the best compound 4-benzoyl-1-(4-fluorobenzyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-1H-pyrrole-2-carboxamide (10g) inhibited HDAC6 with an IC50 of 3.9 nM and superior selectivity over HDAC1 compared to ACY-1215. In vitro, these aroylpyrroles demonstrated promising antiproliferative activities against Hela and SiHa tumor cells. 10g also showed superior metabolic stability compared to ACY-1215 in a microsomal stability study. In summary, this work highlighted the therapeutic potential of aroylpyrrole-based sHDAC6 inhibitors and provided a valuable lead compound in treating cervical cancer.