To Design and Develop Semi-Saturated and Unsaturated Bicyclic Heterocycles for Fragment-Based Drug Discovery (FBDD) Campaigns

  • Nicola Luise

Student thesis: Doctoral ThesisDoctor of Philosophy


The concept of Fragment-Based Drug-Discovery (FBDD) seeks to overcome current issues associated with High-Throughput Screening (HTS) for the identification of novel hits, which are ultimately elaborated into leads and drug candidates. This thesis focuses on the preparation of either novel or commercially limited fragments by engaging diverse synthetic strategies. Moreover, a fragment optimisation process is discussed.

Chapter 2 details the generation of fully unsaturated and semi-saturated bicyclic heterocycles by adopting the concept of reagent- and scaffold-based Diversity-Oriented Synthesis (DOS). This approach was undertaken on three privileged heterocycles, armed with two key functionalities for the bicyclic construction.

Chapter 3 discusses the application of diverse chemistry to construct bicyclic systems from a common intermediate, where pyrazole, a privileged heterocycle able to bind effectively to biological targets, is fused to diverse saturated counterparts. The synthesised fragments present an enhanced sp3-content that can deliver several physicochemical advantages.

Chapter 4 follows the concept of increasing the sp3-portion within molecules that is introduced in chapter 3. However, the synthetic approach is different and based upon in continuous flow hydrogenation of fully unsaturated bicyclic heteroaromatics to deliver semi-saturated systems. The latter are further elaborated by using a simple toolkit of reactions in continuous flow.

Chapter 5 describes the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), which is the sixth leading cause of mortality and it is estimated that 35 million of people are infected. A NMR fragment screen and following X-ray crystallography have identified diverse hits from which an isoquinolinone scaffold was chosen for optimisation. Driven by structural data, structure-activity relationship and supported by literature information, a weak fragment was optimised into a more potent binder of HIV-1 capsid.
Date of Award2019
Original languageEnglish
SupervisorPaul Wyatt (Supervisor)

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