The Identification and Synthesis of Novel Fluorine Containing Heterocycles as Starting-Points of Fragment-Based Drug Discovery

  • Fergus Preston

Student thesis: Doctoral ThesisDoctor of Philosophy


This thesis describes an approach to the identification, design and synthesis of novel fluorine containing heterocyclic fragments to be used as starting points for FragmentBased Drug Discovery programmes. Heterocyclic motifs are common in medicinal chemistry due to their robust synthesis and available chemical transformations. Fluorine incorporation into heterocyclic structures can modulate many physicochemical properties of a compound, not least its ability to block a metabolically labile hotspot. (Chapter 1).

Herein is detailed the filtering of a generated database (GDB) of 26 million compounds to identify a dataset of 11,596 unreported, undocumented fluorinated heterocycles. With the use of a novel elaboratability programme (developed by James Davidson at Vernalis Research Ltd.), we were able to rank the fragments in terms of how readily they could be elaborated. Additionally, with the use of Pipeline Pilot, we were able to calculate the physicochemical properties of the dataset and compare it to commercial fragment libraries which showed that the fragments followed the “Rule of 3” guidelines for fragments. Applying a principal moment of inertia (PMI) plot for the dataset and comparing it to commercial libraries, we demonstrated that we are exploring underreported chemical space. (Chapter 2).

The synthesis of four of these identified fragments is detailed, including reaction optimisation using design of experiment (DoE) approaches as well as efforts for late-stage fluorine incorporation via both traditional and newer methods, such as C – H functionalisation. (Chapter 3).

Lastly, is the development and optimisation of a new photo-redox assisted decarboxylative fluorination strategy of N-heterocyclic acetic acids to their corresponding fluoromethyl counterparts. (Chapter 4).
Date of Award2023
Original languageEnglish
SupervisorPaul Wyatt (Supervisor), Ian Gilbert (Supervisor) & James Davidson (Supervisor)

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