Design of Multi-target Directed Ligands as a Modern Approach for the Development of Innovative Drug Candidates for Alzheimer’s Disease

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with a multi-faceted pathogenesis. So far, the therapeutic paradigm “one-compound-one-target” has failed and despite enormous efforts to elucidate the pathophysiology of AD, the disease is still incurable, with all current medicines only being capable to slow up its progress and ameliorate the quality of life of the patients. The multiple factors involved in AD include amyloid aggregation to form insoluble neurotoxic plaques of Aβ, hyperphosphorylation of tau protein, oxidative stress, calcium imbalance, mitochondrial dysfunction, deterioration of synaptic transmission, and neuronal loss. These factors together accentuate changes in the central nervous system (CNS) homeostasis, starting a complex process of interconnected physiological damage, leading to cognitive and memory impairment and neuronal death. A recent approach for the rational design of new drug candidates, also called multi-target directed ligand (MTDL) approach, has gained increasing attention by many research groups, which have developed a variety of hybrid compounds acting simultaneously on diverse biological targets. In this chapter, we aimed to show some recent advances during the last decade and examples of the exploitation of MTDL approach in the rational design of novel drug candidate prototypes for the treatment of AD.