Advancements in hydrazide-based HDAC inhibitors. A review of recent developments and therapeutic potential

Histone deacetylase (HDAC) impairment is strongly related to various cancers as well as neurodegenerative and inflammatory diseases. Considering HDACs' crucial role as drug targets, over the past decade, the development of HDAC inhibitors (HDACi) has gained significant interest in the pharmaceutical field. To date, five HDAC inhibitors have been approved by the FDA, and many are currently in clinical trials. Despite the common use of hydroxamic acid and 2-aminoanilide groups as zinc-binding groups (ZBGs) in HDAC inhibitors, concerns about their instability, toxicity, and low bioavailability have led researchers to explore alternative ZBGs. Recently, the hydrazide group has emerged as a promising alternative, offering potentially safer properties and fewer off-target effects. This perspective will discuss recent advancements from a medicinal chemistry point of view related to the hydrazide group's role in HDAC inhibitor development, highlighting their pharmaceutical properties, biological activities, and potential benefits in reducing side effects.