Realising Lead-Oriented Synthesis- A ‘Top-Down’ Approach to Synthesising Lead-Like Scaffolds

This report focusses on the concept of lead-oriented synthesis in an attempt to synthesise diverse small molecule scaffolds that target lead-like chemical space. The ‘top-down’ approach was taken, which is a method used within the Marsden and Nelson group where polycyclic assemblies are prepared and then deconstructed to give a library of diverse lead-like molecules. Each lead-like scaffold was synthesised with good stereo/regio control, on a large scale from cheap starting materials, with appropriate molecular properties. Each compound was then investigated for its diversification at points of the scaffold, in the possibility of providing access to a variety of novel-like, sp3-riched compounds suitable for screening. The computational software LLAMA was used throughout the project to help analyse properties and guide the development of three-dimensional compounds.

Chapter 1 discusses the overview of the drug discovery process, detailing the problems faced in the pharmaceutical industry, highlighting the high failure rates for drug candidates possessing certain molecular properties. The ideal molecular properties for drug, leads and fragment compounds is discussed, with the modern synthetic approaches to prepare such lead diverse screening compounds in an efficient manner.

Chapter 2 – 4 details the synthesis of diverse novel scaffolds prepared from robust synthetic methodologies to access a library of compounds with appropriate molecular properties for biological screening. In total 14 scaffolds were synthesised from 28 synthetic operations and 52 novel compounds from a total of 73 synthetic operations. Here the method has produced a library of complex and highly three-dimensional compounds with attention paid to physicochemical and functional group properties, whilst maintaining synthetic efficiency. The library was sent for biological evaluation against five different targets, of which 15 hits were observed. A follow-up library was then produced where 13 compounds were sent for a second round of biological evaluation against the Plasmodium falciparum cells.