Development and application of chemical tools for the design and synthesis of bioactive molecules

In the field of drug design and development, medicinal chemists use a variety of tools to quickly generate a series of hit compounds controlling a specific biological target and culminating in a lead compound. Process chemists seek efficient methods to synthesize the lead compounds provided by the medicinal chemists and using readily available and inexpensive starting materials, shortcuts and simpler routes. With this in mind, we aimed to design, develop and apply chemical tools to generate hit compounds, but also developing new simpler methods to make pharmaceutically relevant compounds. In this context, this thesis has two goals. In the first part, we focused on the enzyme prolyl oligopeptidase, reviewing its involvement in neurological disorders, such as Alzheimer's disease, and the efforts of several researchers to synthesize potent, selective inhibitors resembling the natural substrates of this enzyme. We proposed another method, using small pseudopeptidic and peptidomimetic inhibitors as chemical tools to better understand the shape, size and electronics of inhibitors and generate a more potent, selective prolyl oligopeptidase inhibitor. From our series of compounds, we discovered a few potent and highly selective, covalent inhibitors, one of them pseudo-peptidic (IC50 = 3-7 nM) and the other peptidomimetic (IC50 = 20-700 nM). In the second part of this thesis, with the goal of being able to exploit sugars in medicinal chemistry, we first reviewed the methods that exist to regioselectively functionalize the various hydroxyls of hexopyranosides. We compiled these methods into a table which chemists could consult when they are seeking to perform a specific reaction on a specific sugar. We then proposed to use a hydrogen bond accepting protecting group which can direct subsequent reactions to specific sites on sugars in an effort to reduce the number of protection and deprotection steps. We applied this protecting-directing group and developed methods to regio

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