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.