Design and synthesis of potential inhibitors against dUTPase, a novel drug target for the control of protozoal and bacterial infections.

The enzyme deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is a ubiquitous enzyme that can be considered as the first line of defence against misincorporation of uracil into DNA. Inhibition of dUTPase is lethal in E. coli, S. cervvisiae 'y) and is also likely to be lethal in many other organisms including Plasmodium spp. and Leishmania spp., which are the causative agents of malaria and leishmaniasis respectively. By taking advantage of the differences in the structures of the enzymes in human and in the protozoa, dUTPase was chosen as a chemotherapeutic target. The main aim of this research project was to develop selective inhibitors against leishmanial and plasmodium dUTPases. The research was focused on building a structure-activity relationship study making analogues of previously identified inhibitors within our research group. The work was also supported by molecular modelling studies on the P. falciparum enzyme. The synthesised analogues were nucleosides derivatives of dUMP, which is a proven inhibitor of the leishmanial dUTPase. The different series of compounds included 5'-tritylated nucleosides and acyclic derivatives of dUMP. Three acyclic derivatives showed particular promise against the enzyme with sub-microM Ki values against P. falciparum dUTPase. Some compounds also inhibited in vitro the P. falciparum growth with IC50 values in the microM range. Promising results were obtained also against L. donovani parasite with IC, values in the 10-50 microM range. An antimicrobial screening of compounds previously made in the group was performed by the author against five bacteria strains (E. coli, Ps. aeruginosa, E. faecalis, P. vulgaris and S. aureus) to evaluate the potential application as an antibacterial agent.