Dottorato in SCIENZE FARMACEUTICHE

Titolo della tesi: Development and characterization of novel 2-aroylbenzofuran derivatives as potent and selective human monoamine oxidase B inhibitors: new tools to tackle neurodegenerative diseases

Human monoamine oxidases (hMAOs) are flavin-containing enzymes deputed to the oxidative deamination of exogenous and endogenous amines, including fundamental molecules such as dopamine, serotonin and norepinephrine. Since their discovery in 1928, two isoforms, A and B, have been observed in the human organism and their physiological role has been extensively investigated. Their involvement in the fine regulation of monoamine neurotransmitters concentration has emerged as a pivotal process in the central nervous system. A dysregulation in hMAOs levels or activity can hence contribute to the development of pathological conditions, including neurodegenerative diseases like Parkison’s and Alzheimer’s diseases. Furthermore, hMAOs seem to be involved in the pathogeneses of these conditions also through specific molecular pathways that have not been completely understood yet. In the last decades, researchers have developed hundreds of hMAOs inhibitors based on numerous and different chemical structures. Our research group had developed, in 2019, a series of micromolar inhibitors of hMAO-B based on the benzo[b]thiophen-3-ol scaffold. To further increase the activity of these compounds, we have operated an isosteric replacement of the sulphur atom with an oxygen and other structural modification that have led to the development of eight libraries of novel compounds, all based on the 2-aroylbenzofuran scaffold. Their activities have been evaluated in vitro. The results obtained have shown that the developed compounds are able to potently and selectively inhibit hMAO-, and some compounds have reported IC50 values in the used experimental conditions in the low nanomolar range. These promising results, which must be enriched by the conduction of molecular modelling studies and cell assays for each library, indicate that the 2-aroylbenzofuran structure is a privileged scaffold for the development of hMAOs inhibitors. During the third year of my PhD programme, I have spent six months in the Research and Development (R&D) department of the pharmaceutical industry ITC Production, Pomezia, Italy. During these six months, I have had the chance to contribute to the development and validation of analytical procedure for HPLC, technology transfers and process optimizations for both new and already existing products and conduction of analytical analyses for the control of the batches’ quality. In the last chapter of this work, the validation of an analytical procedure for HPLC for the identification and quantification of sodium gentisate in a promethazine syrup, is briefly reported, as example of the activities carried out during the internship at ITC production.