Dual acting antioxidant hybrids

The objective of this research was to produce single chemical entities with dual pharmacological activity by incorporating an antioxidant substructure into an already active pharmacophore. It was aimed to maintain the well-validated property of the parent compound whilst the antioxidant attachment was utilised for scavenging free radicals. The introductory chapter (Chapter One) introduces free radicals, their beneficial and harmful roles in the biological system and the importance of antioxidants in health and disease prevention. An overview of the research is presented and the advantages of hybrid drug design discussed. Dual acting morphine-antioxidant hybrids as possible analgesics in pain management were explored in this study (Chapter Two). Five morphine-antioxidant analogues were successfully synthesised and isolated. These compounds contain a phenolic or nitroxide antioxidant bound to the morphine framework at the N- or phenolic position through a short hydrocarbon spacer. Pharmacological evaluations demonstrated that the molecule containing the nitroxide, TMIO, attachment showed greater antioxidant activity than morphine with no cytotoxicity. This compound was found to relieve pain over a prolonged period of time after the activity of morphine had worn off, though at a higher dosage than morphine. The second project examined dual acting cytoprotective dithiolethione-antioxidant hybrids (Chapter Three). The ‘control’ dithiolethione was synthesised but the attempted synthesis of a hydrophilic dithiolethione-antioxidant hybrid was unsuccessful. Two dithiolethione-antioxidants, both containing the 2,6- dimethylphenol antioxidant functionality on the C5 dithiolethione ring with either a methyl or phenyl C4 substituent, were subjected to antioxidant testing. At a relatively low concentration, these analogues displayed antioxidant activity.