Design and synthesis of multipotent drugs: application to Alzheimer's disease and benign prostatic hyperplasia

The aim of this thesis was to synthesize multipotent drugs for the treatment of Alzheimer’s disease (AD) and for benign prostatic hyperplasia (BPH), two diseases that affect the elderly. AD is a neurodegenerative disorder that is characterized, among other factors, by loss of cholinergic neurons. Selective activation of M1 receptors through an allosteric site could restore the cholinergic hypofunction, improving the cognition in AD patients. We describe here the discovery and SAR of a novel series of quinone derivatives. Among them, 1 was the most interesting, being a high M1 selective positive allosteric modulator. At 100 nM, 1 triplicated the production of cAMP induced by oxotremorine. Moreover, it inhibited AChE and it displayed antioxidant properties. Site-directed mutagenesis experiments indicated that 1 acts at an allosteric site involving residue F77. Thus, 1 is a promising drug because the M1 activation may offer disease-modifying properties that could address and reduce most of AD hallmarks. BPH is an enlargement of the prostate caused by increased cellular growth. Blockade of α1-ARs is the predominant form of medical therapy for the treatment of the symptoms associated with BPH. α1-ARs are classified into three subtypes. The α1A- and α1D-AR subtypes are predominant in the prostate, while α1B-ARs regulate the blood pressure. Herein, we report the synthesis of quinazoline-derivatives obtained replacing the piperazine ring of doxazosin and prazosin with (S)- or (R)-3-aminopiperidine. The presence of a chiral center in the 3-C position of the piperidine ring allowed us to exploit the importance of stereochemistry in the binding at α1-ARs. It turned out that the S configuration at the 3-C position of the piperidine increases the affinity of the compounds at all three α1-AR subtypes, whereas the configuration at the benzodioxole ring of doxazosin derivatives is not critical for the interaction with α1-ARs.

Design, Synthesis and Characterization of N-Containing Organic Compounds

The needed of new intermediates/products for screening in the fields of drug discovery and material science is the driving force behind the development of new methodologies and technologies. Organic scaffolds are privileged targets for this scouting. Among them a priority place must be attributed to those including nitrogen functionalities in their scaffolds. It comes out that new methodologies, allowing the introduction of the nitrogen atom for the synthesis of an established target or for the curiosity driven researches, will always be welcome. The target of this PhD Thesis’ work is framed within this goal. Accordingly, Chapter 1 reports the preparation of new N-Heteroarylmethyl 3-carboxy-5-hydroxy piperidine scaffold, as potential and selective α-glucosidase inhibitors. The proposed reversible uncompetitive mechanism of inhibition makes them attractive as interesting candidate for drug development. Chapter 2 is more environmentally method-driven research. Eco-friendly studies on the synthesis of enantiomerically pure 1,4-dihydropyridines using “solid” ammonia (magnesium nitride) is reported via classical Hantzch method. Chapter 3 and Chapter 4 may be targeted as the core of the Thesis’s research work. Chapter 3 reports the studies addressed to the synthesis of N-containing heterocycles by using N-trialkylsilylimine/hetero-Diels–Alder (HAD) approach. New eco-friendly methodology as MAOS (Microwave Assisted Organic Synthesis) has been used as witness of our interest to a sustainable chemistry. Theoretical calculations were adopted to fully clarify the reaction mechanism. Chapter 4 is dedicated to picture the most recent studies performed on the application of N-Metallo-ketene imines (metallo= Si, Sn, Al), relatively new intermediates which are becoming very popular, in the preparation of highly functionalized N-containing derivatives, accordingly to the Thesis’ target. Derivatives obtained are designed in such a way that they could be of interest in the field of drug and new material chemistry.