From Kinase Inhibitors to Multitarget Ligands as Powerful Drug Leads for Alzheimer's Disease using Protein‐Templated Synthesis

Multitarget directed ligands (MTDLs) are arising as promising tools to tackle complex diseases. The main goal of this work is to create powerful modulating agents for neurodegenerative disorders. To achieve this aim, we have combined fragments that inhibit key protein kinases involved in the main pathomolecular pathways of Alzheimer's disease (AD) such as tau aggregation, neuroinflammation and decreased neurogenesis, whilst looking for a third action in beta‐secretase (BACE1), responsible of β‐amyloid production. We obtained well‐balanced MTDLs with in vitro activity in three different relevant targets and efficacy in two cellular models of AD. Furthermore, computational studies confirmed how these compounds accommodate adequately into the long and rather narrow BACE1 catalytic site. Finally, we employed in situ click chemistry using BACE1 as protein template as a versatile synthetic tool that allowed us to obtain further MTDLs. Using different small molecules targeting protein kinases and BACE1 templated synthesis, we have obtained well‐balanced multitarget compounds. They have three different biological activities and may be a promising therapeutic approach for the treatment of complex diseases such as AD.