Design and Synthesis of New Chemical Entities to Exploring the Multifactorial Nature of Alzheimer's Disease

Alzheimer's disease (AD) is a multifactorial syndrome, with a complex interplay of genetic and biochemical factors contributing to the cognitive decline. Besides diffuse neuronal loss, AD brain shows protein folding defects, and there is growing evidence that amyloid-? peptide (A?) might trigger the disease process. In parallel, an increasing number of molecular targets, that may play an important role in the expression of its neurotoxicity, is emerging. In particular, the etiopathogenic loop generated by A? and oxidative stress indicates reactive oxygen species (ROS) overproduction as a crucial partner of A? toxicity. Moreover, a correlation between A?, oxidative stress and conformational changes of the transcription factor p53 has been suggested. In this context, (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway plays an important role as the major mechanism of defense in the cell against oxidative or electrophilic stress. Additionally, several evidences showed an attenuation of A?-induced oxidative cell death by means of activation of Nrf2 signaling, calling for a deeper investigation of Nrf2/A? cellular network. Besides that, an excessive glutamatergic activity together with the hyperactivation of extrasynaptic N-methyl-D-aspartate receptors (NMDARs) has been widely documented in AD. In particular, a relationship between NMDARs hyperactivation, ROS production and A? toxicity has been well established in AD. On the basis of these considerations, in order to obtain pharmacological tools to deepen insight into the cross-talk between A? functions and radical species in AD, in this project thesis new chemical entities have been synthesized combining natural privileged molecular fragments, which turned out to be versatile instruments to investigate A? causative role in AD. Furthermore, based on the MTDL (multi-target-directed ligand) approach, aimed to obtain single molecules able to simultaneously hit multiple targets, in this work thesis, multifunctional ligands have been developed by combining the NMDAR antagonist memantine with natural pharmacophores exerting antioxidant and anti-aggregating activities.