RATIONAL DESIGN AND SYNTHESIS OF SMALL MOLECULES TARGETED AGAINST NEURODEGENERATIVE PROCESSES AND DISEASES

Improved sanitary conditions, disease prevention (e.g., vaccinations) and treatment (e.g., antibiotics) have increased life expectancy, up to the 67.2 years value in 2010. Unfortunately, living longer a poor life does not represent anyone’s dream, mostly due to neurodegenerative diseases (NDDs). Alzheimer’s Disease International (ADI) estimates in its 2013 report that there are more than 35 million people with dementia worldwide as of 2010, and that this number will double by 2030 and triplicate by 2050. In industrialized countries the prevalence of Parkinson’s disease (PD) is about 1% for people over 60, with estimates of up to 4% for people in the highest age groups. In 2016 the Centres for Disease Control and Prevention estimated that between 14,000 - 15,000 Americans suffered from Amyotrophic Lateral Sclerosis (ALS). These and other NDDs are the result of neurodegenerative processes, that entail the progressive loss of structure or function of neurons, eventually causing their death. Symptomatic treatment strategies available on the market for NDDs are inadequate, as they offer only temporary relief without changing the ultimate NDD outcome. Effective treatment of NDDs should be based on small molecules able to modulate disease-modifying pathways involved in the development and/or the progression of NDDs, to cause their remission. In my Ph.D. work I focused on four different pathways (each described in a dedicated Chapter) involved in the development of multiple NDDs. With the aim to therapeutically modulate them by promoting and/or inhibiting those targets, I’ve rationally designed and synthetized several classes of compounds. My research group established a multi-disciplinary approach in collaboration with bioinformatics, biologists, pharmacologists and clinicians; thus, my putative NDD treatments were tested by our collaborators in different Universities and Institutes (CIBIO, University of Trento; San Raffaele Research Institute, Milan; Department of Neuroscience, Federico II University, Naples).