Eight-membered cyclic amines as novel scaffolds for drug discovery

Abstract

The research conducted in this PhD thesis is one of the six projects of iDESIGN, an EU-funded European Industrial Doctorate Innovative Training Network (EU-EID-ITN). iDESIGN’s principal research objective was to design and synthesise novel compound libraries of structurally and functionally diverse, three-dimensional molecules with attractive physicochemical properties for early-stage drug discovery. Due to their conformational flexibility and presence in various bioactive natural products, eight-membered cyclic amine derivatives were considered valuable starting points for drug discovery as they represent an underexplored – and therefore underexploited – region of chemical space. Literature compound N-Boc-(Z)-5-oxo-3,4,5,8-tetrahydroazocine was synthesed in five steps, including an optimised ring-closing metathesis reaction as the key step, which was scaled up to gramme scale. By selectively manipulating the embedded enone functionality in this N-Boc-azacyclooctenone parent scaffold, three structurally distinct core scaffolds, comprising an azacyclooctylamine, a family of 8-5/8-6 fused aromatic heterocycles and an 8-5 fused pyrrolidine, were synthesised, each with multiple appendable handles. From these scaffolds, three diverse compound libraries were designed in silico and then prepared via parallel synthesis. Using KNIME and DataWarrior, the compound libraries were designed to display maximum diversity in drug-like physicochemical, structural and molecular shape space, which was validated using principal component analysis and Tanimoto similarity calculations. From the 200 synthesised library compounds, a representative selection was screened for hERG activity, whilst a broad range of measured ElogD values reflected the effort in maximising calculated physicochemical values (e.g., clogP) during in silico library design. All of the library compounds have been submitted to the Haworth Chemically Enabled Compound Collection (HC$^3$), a collaborative screening collection which is maintained by the Birmingham Drug Discovery Hub. Biological screening of these compounds against Mycobacteria and representative ESKAPE pathogens is planned for the near future