Diabetes is a worldwide condition that affects millions of people of all ages and backgrounds. It strikes the rich and the poor, old and young, healthy and sick. Diabetes is one of the largest global health emergencies of the 21st century, where some regions of the world have a much higher occurrence than others. Diabetes occurs when there are increased levels of glucose in the blood due to the lack of insulin, or the inability of the body’s cells to respond to insulin. Type 2 diabetes accounts for approximately 90% of all cases of diabetes worldwide and continues to rise across all world regions. The goal of our research was to investigate two families of heterocyclic compounds that have potential as anti-diabetic agents. We postulated that an anti-diabetic effect might be achieved through the inhibition of complex I of the electron transport chain, which would make oxidative phosphorylation less efficient, and therefore require increased glucose uptake from the blood in order to maintain ATP levels. This would consequently lower blood glucose levels and the inhibitor would thus have a hypoglycaemic effect. Building on findings of previous members of our own research group and collaborators, we developed two families of compounds and evaluated them for their anti-diabetic biological activity. The first family investigated was the arylpiperazine family, which consisted of analogues of the hit compound RTC1. Here, structural variations were performed at five sites on RTC1. The second family explored was the pyrazolopyrimidinone bicycle family, which consisted of analogues of the hit compound RTC53. In this case, structural variations were carried out at two principle sites on RTC53. Hydrophobic, steric, and electronic effects were all explored for both families through the systematic structural modifications. One of the aims of the project, in addition to access a large number of compounds, was to develop improved methods for the synthesis of both families. For the arylpiperazine family, a simpler and higher yielding procedure for their synthesis was achieved. This method no longer required anhydrous conditions or elaborate work-up procedures. For the pyrazolopyrimidinone bicycle family, method development focused on establishing a “one-pot” microwave-assisted synthesis of the pyrazolopyrimidinone bicycle. This avoided the need to isolate and purify intermediates, and reduced total reaction times down to just over 2 hours. Full characterisation of all compounds synthesised was carried out using techniques such as 1H and 13C NMR spectroscopy, including 2D-NMR experiments, X-ray crystal analysis, infrared spectroscopy, and high-resolution mass spectrometry. A structure activity relationship study was performed by testing compounds from both families in (i) a whole cell, functional, glucose uptake assay and (ii) a complex I inhibition assay. The glucose uptake assay measured the amount of tritiated (3H) deoxy-2-glucose taken up by C2C12 mouse muscle cells and quantified the fold change using a protein assay to determine the number of cells present. The complex I assay determined a compound’s ability to inhibit NADH dehydrogenase, complex I of the electron transport chain, by measuring the change in ubiquinone absorbance. Using both these assays, we were able to establish active compounds, which had the potential of developing into anti-diabetic agents, and obtained a better understanding of the influence of structure on this anti-diabetic biological effect.