Multi-target-directed ligands as an innovative therapeutic opportunity for Alzheimer's disease

Alzheimer’s disease (AD) is a major neurodegenerative disease affecting a substantial proportion of elderly population and imposing a significant burden on public health and quality of life. Despite of this, for AD no cure still exists. The finding that it is a complex multifactorial disorder arising from a complex array of neurochemical factors may explain, at least partially, why the currently available drugs, developed according to the classic drug discovery paradigm of "one-molecule-one-target," have turned out to be palliative, rather than curative. In light of this, drug combinations that can act at different levels of the neurotoxic cascade offer new hopes toward effectively treating AD. This finding was also the logical starting point for achieving disease modifying therapeutics by the identification of ligands possessing a multi-modal mechanism of action. Multi-target-directed ligands (MTDLs), which are small molecule rationally designed with the deliberate aim of simultaneously modulating multiple targets in the disease network, should be especially suited to address the extreme complexity of AD etiology. In recent years, the MTDL concept has been exploited by us and others to design different ligands hitting different biological targets. Here, we report on memoquin, a novel MTDL designed by inserting the benzoquinone nucleus of coenzyme Q into a polyamine scaffold. Memoquin furnished us with the ‘proof of concept’ of the MTDL drug discovery approach. In fact, a detailed in vitro and in vivo investigation allowed us to demonstrate that memoquin combats AD on different crucial fronts: it inhibits acetylcholinesterase, amyloid production and aggregation, and also oxidative stress. Memoquin was also the lead molecule for an optimization program aimed at developing novel MTDLs with more balanced affinity profiles and physicochemical properties consistent with good oral absorption. The results obtained further support the potential for the development of efficacious multi-targeted drug candidates against AD.