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

Histone deacetylase inhibitors (HDACIs) are responsible forcontrolling gene expression by modulating the acetylationstatus of histone proteins. Furthermore, they modulate the ac-tivity of cytoplasmic non-histone proteins. Due to the involve-ment of HDACs in neurodevelopment, memory formation, andcognitive processes, HDACIs have been suggested as innova-tive agents for the treatment of neurodegenerative disorderssuch as Alzheimer’s disease (AD). Given their mechanisms ofaction and the complex nature of AD, HDACIs have been pro-posed for the design of novel multitarget ligands (MTLs). Tothis aim, the fragment responsible for HDAC inhibition hasbeen coupled with other structures that are able to provideadditional biological actions, such as antioxidant activity or theinhibition of phosphodiesterase 5, transglutaminase 2, and gly-cogen synthase kinase 3b. Herein we discuss recent efforts todesign HDACI-based MTLs as potential disease-modifying enti-ties.