Realisation of CNS-relevant Molecular Scaffolds Using an Integrated Computational and Synthetic Approach

The physicochemical properties of leads are of vital importance to obtain drugs with the desired therapeutic effect. In central nervous system (CNS) drug discovery, the properties of CNS-leads are even more restricted due to the fact that the resulting drugs must cross the blood-brain barrier (BBB). This thesis is focused on the development of computational and synthetic approaches that can assist the identification of molecular scaffolds that, after decoration, can yield high-quality lead-like molecules for CNS drug discovery. Chapter 1 describes the drug discovery process and its productivity decline. It discusses the importance of physicochemical properties in the early stages, particularly for CNS-drugs. It describes the current computational methodologies and synthetic approaches used to obtain high-quality lead-like molecules. Chapter 2 features the development and validation of a novel computational tool to assist the identification of scaffolds likely to yield high-quality lead-like molecules for CNS drug discovery. Successively, it describes the exemplification of this tool using a Lead-Oriented Synthesis (LOS) approach. Chapter 3 details the elaboration of a novel LOS approach for the synthesis of diverse scaffolds able to yield lead-like molecules with the desired properties for CNS. This approach involves the preparation of highly functionalised cyclisation precursors. Subsequently, different cyclisation reactions are investigated and optimised to yield a library of different scaffolds. The previously developed computational tool is used to assess the value of the scaffolds for CNS. Chapter 4 shows the decoration of some of the prior scaffolds to produce diverse derived molecules, which are used for ligand discovery against the CNS-target BACE1 (β-site amyloid precursor protein cleaving enzyme 1). Chapter 5 describes the methods and materials for the preparation of the computational tool, for the synthesis of all the scaffolds and derived compounds and for the assessment of the biological activity.