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 create powerful modulating agents for neurodegenerative disorders. To achieve aim, we have combined fragments that inhibit key protein kinases involved in the pathomolecular pathways Alzheimer's disease (AD) such tau aggregation, neuroinflammation and decreased neurogenesis, whilst looking a third action beta-secretase (BACE1), responsible β-amyloid production. We obtained well-balanced MTDLs with vitro activity three different relevant targets efficacy two cellular models AD. Furthermore, computational studies confirmed how these compounds accommodate adequately into long rather narrow BACE1 catalytic site. Finally, employed situ click chemistry using template versatile synthetic tool allowed us obtain further MTDLs.