A rational design of new multi-target-directed-ligands for the treatment of Alzheimer's disease

Alzheimer’s disease (AD) is a multifactorial disease and an age-related neurodegenerative disorder clinically characterized by loss of memory and progressive deficits in different cognitive domains. Much effort has been devoted to elucidate the relationships between the hallmarks of the disease, that is, i) amyloid-β (Aβ) plaques, a massive deposit of amyloid peptide generated by successive cleavage of the amyloid precursor protein (APP) by β-(BACE-1) and γ-secretase, ii) neurofibrillary tangles (NFT), and iii) loss of neurons in the hippocampus and nucleus basalis of Maynart. AD is characterized by a pronounced degradation of the cholinergic system and by alteration in other neurotransmitter systems such as the glutamatergic and serotoninergic ones. Despite considerable scientific progress, the aetiology of AD is still unknown and speculated about. The current pharmacological approach is mainly based on the so-called “cholinergic hypothesis”, which states that restoration of the cholinergic functionalities can be achieved by cholinomimetic agents acting at the synaptic level. A more recent strategy, proposes that it is possible the design and synthesis of multi-target-directed-ligands (MTDL), single molecules able to hit several targets responsible for the multifaceted aetiology of AD.1 Following this strategy, our group has been involved for a long time in the design and synthesis of compounds for AD treatment. The prototype of such derivatives was caproctamine (1).2 SAR studies carried out on 1 structure allowed us to provide derivatives endowed with multipotent biological profile.3-5 By exploiting “the frozen analogue approach” we subsequently designed and synthesized new MTDL’s derived from 1 and able to hit several peculiar targets involved in AD pathogenesis. The results of this research will be illustrated.