Investigations Into the Synthesis, Physicochemical Characterization and Enzymology of Substituted Benzoxaboroles, Phosphonic-boronic acid anhydrides and Exoglycals

Abstract

This thesis describes the design, synthesis, and evaluation of novel chemical scaffolds for the development of potent enzyme inhibitors. The work explores the strategic incorporation of boron and phosphorus to investigate their effect on the physicochemical properties and biological activity. Three distinct compound classes were investigated: benzoxaborole-phosphorus(III) hybrids, phosphonic acid-boronic acid anhydrides, and exoglycal derivatives. A one-pot synthetic route was developed to access previously unreported benzoxaborole-phosphorus(III) hybrids. These compounds demonstrated enhanced aqueous stability and oxidative resistance compared to conventional boronic acids. Subsequently, phosphonic acid-boronic acid anhydrides were introduced as a novel scaffold, where the appended phosphorus group was shown to affect the boron atom's acidity and stability. Biological evaluation demonstrated these boron-phosphorus compounds to be promising inhibitors of Class A, C, and D β-lactamases. A series of exoglycals were synthesized as transition-state analogues for glycoside hydrolase family 3 (GH3). One compound exhibited potent competitive inhibition against the model enzyme EryBI, with affinity comparable to the natural substrate, by mimicking the half-chair conformation of the hydrolysis transition state.