Abstract/Summary

It has been predicted that by 2050, 10 million deaths will occur as a result of resistant microbials. This is a growing concern which is creating an urgent need for the development of new antimicrobials as well as additional selective media for the identification of these bacteria. When designing new antimicrobial compounds, their selectivity to different bacterial strains, and their solubilities, must be optimised, for example through prodrug strategies. Since some bacterial strains are documented to have different levels of glycosidase enzymes, glycoside based prodrugs have proven of interest in antibacterial strategies. The overarching aim of this work was therefore to design, synthesise and analyse a range of glycoside prodrugs both as antibacterial agents and agents for the selective recovery of bacteria. Through this work, structure-activity relationships for the parent compounds and the prodrugs against a range of gram-negative and gram-positive bacteria could also be determined based on minimum inhibitory concentration values which were determined using a bioscreen or agar method. Therefore, β-glucosides and β-galactosides of 2-benzylphenol and bis(2-hydroxyphenyl)methane were synthesised using an aq. Michael addition method. All the β-glycosides had MIC values of >128 μg/mL. 2-Benzylphenol was found to have MIC values of 64 μg/mL for Streptococcus agalactiae, Streptococcus pneumoniae and Streptococcus pyogenes which is similar to the MIC value for cefaclor and cefaoxil, which are used in the clinic. Using a different synthetic route based on phase transfer catalysis, β-glucosides and β-galactosides of 7-hydroxyflavone, chrysin and 7,8-dihydroxyflavone were synthesised. All the β-glycosides had MIC values of >128 μg/mL whilst 7,8-dihydroxyflavone and 7-hydroxyflavone had values of 25 and 6.25 μg/mL for Staphylococcus epidermidis and 50 and 12.5 μg/mL for Staphylococcus aureus, respectively. These compounds were also tested using an MTT assay, against the breast cancer MCF-7 and MDA-MB231 cell lines to obtain toxicity iii data to evaluate their anticancer properties. The preliminary cell assays concluded that all compounds had an IC50 >2 mM. 1,2,3-Triazole derivatives of azidothymidine were also prepared using ‘click’ chemistry, with copper catalysed reactions affording the 4’ isomers, and ruthenium catalysed reactions affording the 5’ isomers. 3’-Deoxy-3’-(5-hydroxymethyl-1,2,3-triazol-1-yl)-β-D-thymidine had comparable MIC values to azidothymidine, against Escherichia coli and Klebsiella pneumoniae, specifically 8 and 0.5 μg/mL, respectively. To probe the antiviral activity of these compounds, the compounds were fitted using Pymol into the active site of the HIV reverse transcriptase enzyme, which is central for antiviral activity. All compounds were found to fit into the active site; however, further studies are needed to definitively determine their antiviral activity. The work presented in this report display further advances the knowledge of structure-activity relationships within the three different classes of compounds. This can be used to further design better antimicrobials for potential use as selective media or clinical uses.