Prodrug Self Associating Amphiphiles to Target Anti-Microbial Resistance

Due to rising antimicrobial resistance (AMR), there is a need for new therapeutic approaches to tackle resistance mechanisms seen in constantly evolving bacteria and fungi. This research approaches this through the combination of the strong self-associative nature of supramolecule self-associating amphiphiles and the traditional antifungal drug fluconazole, not through coformulation but through direct covalent linkage which offers unique advantages. In this study we synthesise and purify two analogous fluconazole SSAs (Compound 4 and compound 5) and probe them for their self-associative behaviour both within the solid, and solution state. In the solid state we see that the compound 5 forms dimers leaving the fluconazole end of the molecule free (useful for potential binding kinetics). With the addition of fluconazole to these SSAs we still see self association in solution evidenced by loss in signal using quantitative NMR spectroscopy methods both in DMSO and aqueous solvents. This is further supported by larger aggregates being observed using dynamic light scattering methods. The aggregate hydrodynamic diameters and distributions were shown vary depending on annealing methods used, likely due to the additional complexity of the bulky fluconazole appendage requiring more conformational rearrangement. Finally, the zeta potentials suggest stable aggregates achievable with the correct annealing methods with hints of time dependent stabilisation. Unfortunately no biological data is presented here but the compounds have been submitted for biological testing and results are pending. This thesis underpins the synthetic methods and physiochemical information required to help underpin, support and hopefully explain some of the future biological results that will be received shortly.