Medicinal chemistry of sirtuin inhibitors

As members of Class III histone deacetylases (HDACs), sirtuins use stoichiometric nicotinamide adenine dinucleotide (NAD⁺) to remove the acetyl group from N-acetyl-lysines of histones or non-histone proteins. Sirtuins have been implicated in metabolic diseases, cancer, and neurodegenerative diseases, constituting a promising target for drug discovery. While the early sirtuin inhibitors mimicked NAD⁺ or substrate peptides, high-throughput and in silico screenings have identified a wide range of core structures, many of which have been subjected to medicinal chemistry efforts. This review outlines inhibitor chemotypes, and their chemical modifications and biological evaluations, highlighting strategies to enhance inhibitory activity and selectivity among isoforms.