Design and synthesis of n-containing bicyclic scaffolds for library generation

Conway, Órla M. (2022). Design and synthesis of n-containing bicyclic scaffolds for library generation. University of Birmingham. Ph.D.

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Abstract

In recent years, the field of drug discovery has begun to move away from targets which have traditionally been deemed “druggable” and has placed a focus on the exploration of novel areas of chemical space. However, efforts to access these challenging targets have been continually afflicted with low hit rates in early-stage discovery and subsequently high rates of attrition during clinical trials. Numerous studies have found that a lack of scaffold diversity coupled with poor physiochemical properties regarding bioavailability are major factors contributing to the high compound failure rates.

In order to circumvent these issues, drug discovery strategies such as lead- and diversity-orientated synthesis approaches have been developed to control and direct the molecular properties of compounds within a screening library to occupy relevant, under-explored areas of chemical space while synthesising structurally complex and diverse compound collections.

This thesis reports the development of a step-efficient and robust synthetic route for the synthesis of bicyclic, N-heterocycle-containing scaffolds with stereochemical control. The designed methodology takes stereochemically controlled 2,4-cis-azetidine rings and through a series of high-yielding transformations gives rise to two distinct bicyclic scaffolds; a 4,6-fused system and a 5,6-bridged system (Figure (i)). In silico library enumeration was carried out on these novel scaffolds using data analytics software to yield large sets of virtual compounds which were filtered based on their molecular properties to great small diverse sets for the creation of drug-like screening libraries.

The novel scaffold systems were decorated using a diversity-orientated synthesis approach to access 177 compounds which display a high degree of structural diversity and three dimensionality and possess inherently drug-like molecular properties. The resultant compounds have been submitted for early-stage biological screening and preliminary results show that several members of the novel compound libraries display a biologically significant effect on the rate of bacterial growth.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):