Histone Deacetylase Inhibitors as Multitarget Ligands: New Players in Alzheimer's Disease Drug Discovery?

Histone deacetylase inhibitors (HDACIs) are responsible for controlling gene expression by modulating the acetylation status of histone proteins. Furthermore, they modulate the activity of cytoplasmic non‐histone proteins. Due to the involvement of HDACs in neurodevelopment, memory formation, and cognitive processes, HDACIs have been suggested as innovative agents for the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). Given their mechanisms of action and the complex nature of AD, HDACIs have been proposed for the design of novel multitarget ligands (MTLs). To this aim, the fragment responsible for HDAC inhibition has been coupled with other structures that are able to provide additional biological actions, such as antioxidant activity or the inhibition of phosphodiesterase 5, transglutaminase 2, and glycogen synthase kinase 3β. Herein we discuss recent efforts to design HDACI‐based MTLs as potential disease‐modifying entities. Multitarget drug design is currently one of the main strategies used to obtain new anti‐Alzheimer′s disease (AD) compounds. Based on the known connections between epigenetic and “classical” anti‐AD targets, histone deacetylase inhibitors (HDACIs) have been used to design innovative multitarget ligands (MTLs). Herein we discuss the rationale for the various design strategies applied, highlighting examples of recently reported HDACI‐based MTLs.