|Tipo di tesi||Tesi di laurea magistrale|
|Titolo||Reazione di Cicloaddizione [3 + 2] per la sintesi di α-imminofosfonati biciclici quali ligandi del recettore imidazolinico I2 per il trattamento della malattia di Alzheimer (AD)|
|Titolo in inglese||[3 + 2] Cycloaddition reaction for the synthesis of bicyclic α-iminophosphonates Imidazoline I2 Receptor ligands to fight Alzheimer’s Disease (AD)|
|Struttura||Dipartimento di Scienze della Vita|
|Corso di studi||CHIMICA E TECNOLOGIA FARMACEUTICHE (D.M. 270/04)|
|Data inizio appello||2022-04-11|
|Disponibilità||Embargo di 3 anni|
|Data di rilascio||2025-04-11|
Il morbo di Alzheimer (AD) è una malattia neurodegenerativa progressiva e rappresenta la principale causa di demenza senile e una delle cause più comuni di disabilità e perdita di indipendenza negli anziani. L'Organizzazione Mondiale della Sanità (OMS) stima che il costo dei disturbi associati a demenza nella sola Unione Europea (UE) superi i 160 miliardi di euro all'anno. Questi costi sono destinati ad aumentare in maniera drammatica a causa dell'invecchiamento demografico della popolazione europea determinando un serio problema di sostenibilità dei Sistemi Sanitari Nazionali.
Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder and represents nowadays the leading cause of senile dementia and one of the most common causes of disability and loss of independence in elderly people. The World Health Organization (WHO) estimates the cost of dementia disorders in the European Union (EU) alone to be more than 160 Billion Euro per year. This cost will continue to rise dramatically as the numbers of people with dementia in EU are projected to nearly double every 20 years, due to Europe’s demographic aging. The limited efficacy of the current drugs in preventing the progress of the disease and the multiple etiologies and pathophysiological processes of AD has prompted the medicinal chemists to look for new therapeutic targets. Recent findings unveil the imidazoline I2 receptors (I2-IR) as a novel strategy to face unmet neurodegenerative diseases. Recently, the research group of Prof. Carmen Escolano, at the University of Barcelona, reported on a structurally new family of (2-imidazolin-4-yl)phosphonates (MCRs) as high affinity Imidazoline I2 Receptor Ligands (ACS chem Neurosc 2016) showing beneficial effects in behavior and cognition (Neurotherapeutics 2019). The aim of my master thesis work, carried out in Prof. Escolano’s lab, was to contribute to the SAR studies of a new class of structurally related α-iminophosphonates (Bicyclic series) as potential Imidazoline I2 Receptor ligands. In particular, I focused my work on the synthesis of bicyclic α-benzyl-iminophosphonates (B). The α-iminophosphonates were synthetized by procedures that fulfil the principles of Green Chemistry, starting from an α-substituted diethyl isocyanomethylphosphonate and diverse N-substituted maleimides, using the previously reported diastereoselective [3 + 2] cycloaddition reaction, under AgOAc catalysis (Organic & Biomolecular Chemistry 2013). At the same time, I was asked to deeply investigate this [3+2] cycloaddition reaction as regards the formation of side-products. In fact, during the synthesis of the bicyclic series (B) three compounds were observed: the bicycle (B), as expected, and, in addition, two diastereomeric by-products coming from the addition of a maleimide on the bicycle (BMA) which have not been described before. Three different reaction conditions were explored in order to study the reactivity of position 3a on diverse substituted bicycles with regards the formation of the two by-products (BMA). This study will allow to isolate the two diastereomers to unequivocally determine their three-dimensional structure through single crystal X-ray diffraction.