Direct- And Spacer-Coupled Codrug Strategies for the Treatment of Alzheimer’s Disease

Over the last years, the ‘multi-target-directed ligand’ strategy has been exploited by many researchers to develop novel attractive tools in the search for new agents for Alzheimer’s disease (AD). Small molecules that concurrently target and modulate AD multiple pathological factors can be synthesized using such strategy. This paper will mainly focus on direct- and spacer-coupled codrug approaches that we recently rationally used to design multifunctional molecules able to contrast oxidative stress, neuroinflammation, glutamate toxicity, and metal dyshomeostasis, as a function of the structural elements introduced in the chemical framework. Although the potential use of these strategies needs further exhaustive studies, it may offer a promising therapeutic alternative for increasing neuronal protection and preventing AD progression.