Multitarget strategies in search of novel drug candidates against Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the most common form of dementia and one of the most important health-care problems in the world, due to its high prevalence and unaffordable personal and economic impact. Moreover, current commercialised treatments are only symptomatic, but are not capable of preventing, curing or even delaying the disease progression. Because AD arises from a complex network of pathological events, such as dysfunction in neurotransmitter systems (mainly cholinergic and glutamatergic), β-amyloid and tau proteins disorders, oxidative stress or neuroinflammation, amongst others, the traditional medicinal chemistry paradigm of “one molecule-one target” is increasingly regarded as clearly ineffective. On the contrary, it becomes evident that a more comprehensive, complex pharmacological approach is needed to tackle AD. As a consequence, the use of multitarget directed ligands, where one single molecule is able to interact simultaneously with multiple targets of the pathological network, is emerging as a promising and more realistic way to confront this disease. In this context, the purpose of the present Thesis was the design, synthesis and biological evaluation of three novel families of compounds, endowed with multitarget biological profile, in order to find novel treatments for AD: 1) firstly, a new series of compounds designed by substitution of the rhein subunit of a rhein–huprine hybrid lead, previously developed in our group, by more simplified scaffolds, with the aim of finding optimized hybrids with reduced lipophilicity and better drug-like properties, while maintaining favourable activities against cholinesterases, BACE1, β- amyloid and tau aggregation, and antioxidant properties; 2) secondly, a novel family of huprine- derived hybrids, designed to perform a dual binding site interaction within BACE1 through the linkage of a huprine moiety to new scaffolds, selected by their predicted binding affinities towards a secondary transient pocket in BACE1, which were expected to combine cholinesterases and BACE1 inhibitory activities, as well as activity against β-amyloid and tau aggregation, and antioxidant properties; 3) finally, a family of huprine–TPPU and tacrine–TPPU hybrids, which were designed to be dual inhibitors of acetylcholinesterase (AChE) and soluble epoxide hydrolase (sEH). The blood–brain barrier permeability was also assessed for all these compounds, as it is a crucial factor for drugs acting in the central nervous system, while other important physicochemical and pharmacokinetic parameters, such as solubility and microsomal stability were determined for the latter series of compounds. Also, the toxicity of some compounds was evaluated. Finally, using the same assay that was employed for the determination of the β-amyloid and tau antiaggregating activity of the first two families and other compounds synthesised by our group, we demonstrated that a single compound can be able of inhibiting the aggregation of different types of amyloid-prone proteins, with these results supporting the notion that common mechanisms exist for the aggregation of different amyloidogenic proteins and that a generic treatment of conformational diseases is possible.