Reactive metabolites of xenobiotics pose a risk in pharmaceutical development. Many reactive metabolites are capable of forming adducts with cellular macromolecules which can result in toxicity. For example, aromatic amines have been demonstrated to form adducts with DNA leading to genotoxicity. Hydrolysis of amide and cleavage of sulphonamide bonds can act as a source of aromatic amine metabolites which can undergo further bioactivation. It has also been suggested that acyl glucuronide conjugates of carboxylic acid-containing drugs, induce hepatotoxicity through adduct formation. Due to the similar chemistry, it is proposed that acyl glucosides will display similar adduct formation/potential toxicity. Better understanding of the factors that affect the reactivity of xenobiotics will lead to improved safety and reduce late stage attrition rates in the pharmaceutical industry.

Within this thesis, the nucleophilic reactivity of amides, sulphonamides and acyl glucosides were investigated using a combination of in vitro and in silico techniques. A congeneric series of fifty five sulphonamides were synthesised and five sulphonamides were determined to undergo glutathione-mediated cleavage. Cleavage of N-(4-trifluoromethylphenyl) benzenesulphonamide, demonstrates that the amine portion of the sulphonamide bond plays a role in determining whether the sulphonamide is cleaved.

Comparison of the amide hydrolysis activity of multiple human and animal derived in vitro models, demonstrated the potential of minipig systems as a model for detecting human in vivo relevant metabolites. QSMR and active site models were developed for the prediction of amide hydrolysis and descriptors such as partition coefficient, partial atomic charges and hydrogen bonding were highlighted as important descriptors. The reaction mechanism of the transacylation of acyl glucosides identified key descriptors for predicting the rate of degradation including the ELUMO, electrophilicity index and the calculated activation energy. In addition, comparison of the acyl glucosides to equivalent acyl glucuronides series identified differences in geometry and activation energy between the series.