This thesis project is part of a research line conducted by the Med Chem Lab of the Department of Pharmaceutical Sciences of the University of Pavia. The project consists in the design, synthesis and characterization of new chemical entities with an arylalkenylpiperidine structure as potential modulators of the Sigma-1 receptor (S1R) and new neuroprotective agents. The work was divided into four phases. Specifically, the first phase consisted in the design of new derivatives of a library of multi-target molecules previously developed by the Med Chem Lab: starting from a series of arylalkylaminoketones I designed some arylalkenylpiperidines bearing different substituents on the double bond and divided in two series characterized by different lengths of the carbon chain. This has been done to evaluate the effects of the introduction of these portions on the general scaffold, and to expand the knowledge on potential modulators of the Sigma-1 receptor. The second phase involved a virtual study of these molecules using “SIGMAP”, a software designed to predict, through artificial intelligence, the possible affinity towards the Sigma-1 receptor. Before submitting the molecules of interest to the program, I performed an evaluation of the software, in order to investigate its reliability: I verified that the software is able to discriminate binders and non-binders within an internal library of the laboratory consisting of molecules with known affinity toward the Sigma-1 receptor. Then, I submitted the new molecules designed by me and they were almost all classified as binders of the Sigma-1 receptor, with few exceptions, probably due to a bug of the software that isomerizes the double bond. The third step was the retrosynthetic analysis, to plan the subsequent syntheses, of my compounds of interest. The result of this process was the identification of a common synthetic route for all the compounds. The synthesis uses some arylalkylaminoketones as intermediates, which can be converted into the corresponding arylalkylaminoalcohols, by reduction or nucleophilic addition, and finally into the arylalkenylpiperidines of my interest by dehydration. For a part of the compounds, identified as series I, an alternative shorter synthetic route was identified, whose key reaction is the formation of an enamine by condensation between an aldehyde and an amine. The fourth and final phase of my thesis project was the synthesis and chemical characterization of some of the designed compounds. The syntheses for the compounds belonging to series II was achieved without particular issues, and in particular, a reaction with a “solvent-free” approach was also investigated, in order to improve the eco-sustainability of the chemical process. The obtained molecules were subsequently salified as hydrochlorides, for future biochemical characterization. For the compounds belonging to series I, preliminary tests of the enamine formation reaction were carried out using 2-phenylpropionaldehyde and naproxenal (obtained from naproxen) as model aldehydes, more easily accessible than the substrates necessary to obtain the designed compounds. Although three distinct protocols were evaluated, the desired products have not been isolated yet, and therefore these tests will constitute the starting point for future studies. In conclusion, the aim of my thesis project has been pursued through conventional approaches integrated with other more innovative and eco-sustainable ones, demonstrating how it is possible to constructively combine the advantages of different techniques and approaches, thus obtaining new information useful for pursuing research on new molecules potentially useful in the treatment of neurodegenerative diseases.
Questo progetto di tesi si colloca all’interno di una linea di ricerca condotta dal Med Chem Lab del Dipartimento di Scienze del Farmaco dell’Università di Pavia. Il progetto consiste nel disegno, sintesi e caratterizzazione di nuove entità chimiche a struttura arilalchenilpiperidinica quali possibili modulatori del recettore Sigma-1 (S1R) e agenti neuroprotettivi. Il lavoro si è articolato in quattro fasi. La prima fase del lavoro è consistita nel disegno di nuovi derivati di una libreria di molecole multi-target precedentemente sviluppata dal Med Chem Lab: a partire da una serie di arilalchilamminochetoni ho disegnato delle arilalchenilpiperidine portanti diversi sostituenti sul doppio legame e suddivise in due serie caratterizzate da una diversa lunghezza della catena carboniosa. Questo è stato fatto per valutare gli effetti dell’introduzione di queste porzioni all’interno dello scaffold generale ed espandere ulteriormente le conoscenze verso i potenziali modulatori del S1R. La seconda fase ha previsto uno studio virtuale delle molecole oggetto della mia tesi tramite l’utilizzo di “SIGMAP”, un software progettato per predire, tramite intelligenza artificiale, la possibile affinità di una molecola verso il S1R. Prima di sottoporre le mie molecole di interesse al programma ho eseguito una valutazione del software, al fine di indagarne l’attendibilità. Successivamente, le nuove molecole da me disegnate sono state sottoposte al software, il quale le ha individuate come possibili ligandi del S1R, ad eccezione di poche strutture, probabilmente a causa di un “bug” del programma che porta ad isomerizzare il doppio legame. La terza fase è stata l’analisi retrosintetica, per pianificare poi le successive sintesi, dei miei composti di interesse. Il risultato di questo processo è stata l’identificazione di una via sintetica comune per tutti i composti. La sintesi sfrutta come intermedi alcuni arilalchilamminochetoni che possono essere convertiti nei corrispondenti arilalchilamminoalcoli, mediante riduzione o addizione nucleofila, ed infine nelle arilalchenilpiperidine di mio interesse tramite disidratazione. Per una parte dei composti, identificati come serie I, è stata identificata una via di sintesi alternativa, la cui reazione chiave è la formazione di un’enammina per condensazione tra un’aldeide e un’ammina. La quarta ed ultima fase del mio progetto di tesi è stata la sintesi e la caratterizzazione chimica di alcuni dei composti disegnati. Le sintesi per i composti appartenenti alla serie II sono avvenute senza particolari criticità, ed in particolare, è stata indagata anche una reazione con approccio “solvent-free”, così da migliorare l’ecosostenibilità del processo chimico. Le molecole ottenute sono state successivamente salificate come cloridrati, in attesa della caratterizzazione biochimica. Per i composti appartenenti alla serie I sono state effettuate delle prove della reazione di formazione dell’enammina utilizzando la 2-fenilpropionaldeide e la naprossaldeide (ottenuta dal naprossene) come aldeidi modello, più facilmente accessibili rispetto ai substrati necessari per l’ottenimento dei composti disegnati. Nonostante siano stati valutati tre distinti protocolli, i prodotti desiderati non sono ancora stati isolati, e pertanto queste prove costituiranno il punto di partenza per studi futuri. Per concludere, l’obbiettivo del mio progetto di tesi è stato perseguito tramite approcci convenzionali integrati da altri più innovativi ed eco-sostenibili, dimostrando come sia possibile combinare tra loro in maniera costruttiva i vantaggi di tecniche ed approcci differenti, ottenendo così nuove informazioni utili per il perseguimento delle ricerche di nuove molecole potenzialmente utili nel trattamento delle patologie neurodegenerative.
Disegno e sintesi di nuovi modulatori dei recettori Sigma a struttura arilalchenilpiperidinica.
BONIZZONI, FILIPPO
2024/2025
Abstract
This thesis project is part of a research line conducted by the Med Chem Lab of the Department of Pharmaceutical Sciences of the University of Pavia. The project consists in the design, synthesis and characterization of new chemical entities with an arylalkenylpiperidine structure as potential modulators of the Sigma-1 receptor (S1R) and new neuroprotective agents. The work was divided into four phases. Specifically, the first phase consisted in the design of new derivatives of a library of multi-target molecules previously developed by the Med Chem Lab: starting from a series of arylalkylaminoketones I designed some arylalkenylpiperidines bearing different substituents on the double bond and divided in two series characterized by different lengths of the carbon chain. This has been done to evaluate the effects of the introduction of these portions on the general scaffold, and to expand the knowledge on potential modulators of the Sigma-1 receptor. The second phase involved a virtual study of these molecules using “SIGMAP”, a software designed to predict, through artificial intelligence, the possible affinity towards the Sigma-1 receptor. Before submitting the molecules of interest to the program, I performed an evaluation of the software, in order to investigate its reliability: I verified that the software is able to discriminate binders and non-binders within an internal library of the laboratory consisting of molecules with known affinity toward the Sigma-1 receptor. Then, I submitted the new molecules designed by me and they were almost all classified as binders of the Sigma-1 receptor, with few exceptions, probably due to a bug of the software that isomerizes the double bond. The third step was the retrosynthetic analysis, to plan the subsequent syntheses, of my compounds of interest. The result of this process was the identification of a common synthetic route for all the compounds. The synthesis uses some arylalkylaminoketones as intermediates, which can be converted into the corresponding arylalkylaminoalcohols, by reduction or nucleophilic addition, and finally into the arylalkenylpiperidines of my interest by dehydration. For a part of the compounds, identified as series I, an alternative shorter synthetic route was identified, whose key reaction is the formation of an enamine by condensation between an aldehyde and an amine. The fourth and final phase of my thesis project was the synthesis and chemical characterization of some of the designed compounds. The syntheses for the compounds belonging to series II was achieved without particular issues, and in particular, a reaction with a “solvent-free” approach was also investigated, in order to improve the eco-sustainability of the chemical process. The obtained molecules were subsequently salified as hydrochlorides, for future biochemical characterization. For the compounds belonging to series I, preliminary tests of the enamine formation reaction were carried out using 2-phenylpropionaldehyde and naproxenal (obtained from naproxen) as model aldehydes, more easily accessible than the substrates necessary to obtain the designed compounds. Although three distinct protocols were evaluated, the desired products have not been isolated yet, and therefore these tests will constitute the starting point for future studies. In conclusion, the aim of my thesis project has been pursued through conventional approaches integrated with other more innovative and eco-sustainable ones, demonstrating how it is possible to constructively combine the advantages of different techniques and approaches, thus obtaining new information useful for pursuing research on new molecules potentially useful in the treatment of neurodegenerative diseases.| File | Dimensione | Formato | |
|---|---|---|---|
|
Tesi_Filippo Bonizzoni.pdf
non disponibili
Dimensione
2.65 MB
Formato
Adobe PDF
|
2.65 MB | Adobe PDF | Richiedi una copia |
È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
Per maggiori informazioni e per verifiche sull'eventuale disponibilità del file scrivere a: unitesi@unipv.it.
https://hdl.handle.net/20.500.14239/29788