Multicomponent Reactions for Multitargeted Compounds for Alzheimer's Disease

Alzheimer's Disease (AD) is a multifactorial and fatal neurodegenerative disorder affecting around 35 million people worldwide, which is characterized by decline of cholinergic function, deregulation of amyloid beta (A beta) oligomers formation and A beta fibril deposition. Multi-Target-Directed Ligands (MTDLs) have emerged as an original strategy for developing new therapeutic agents on AD. Multicomponent Reactions (MCRs) are a useful alternative to sequential multistep syntheses, allowing scaffold diversity and a rapid and easy access to biologically relevant compounds. The biological diversity of MCRs is very rich providing great possibilities for researchers interested in bioactive small molecular weight compounds. Since the MTDL strategy has been used to develop compounds endowed with the capacity to interact with different targets, versatile compound libraries may be obtained by MCRs according to the well established features of each target. Thus, either MTDLs or monotarget compounds have been developed by MCRs to address different factors implicated in AD. This work focuses on antioxidants, calcium channel modulators, both AChE and BuChE inhibitors, BACE1 inhibitors, and modulators of the nuclear factor (erythroid-derived 2)-like 2. First, we discuss the Biginelli reaction and its use for developing new interesting compounds for AD, followed by the contribution of Ugi reaction and, finally, the interest of other MCRs in the same topic.