Inhibitors of purine and pyrimidine pathways

The purine salvage pathway offers potential enzyme targets for novel antimalarial agents. Blocking the pathway by which adenosine obtained from the host cell is converted to the purine nucleotides required for nucleic acid synthesis is likely to be highly detrimental to parasite survival. Research has been carried out into finding inhibitors for the first two enzymes in the pathway. Coformycins have been identified as inhibitors of adenosine deaminase, while immucillins inhibit purine nucleoside phosphorylases. However, there has been far greater research into developing inhibitors against the third enzyme in the pathway—hypoxanthine-guanine-[xanthine] phosphoribosyl transferase. These studies have mostly focused on the design of phosphonate, bisphosphonate, and aza bisphosphonate inhibitors, as well as relevant phosphoramidate prodrugs. Some immucillins have also been shown to act as inhibitors. By contrast, little research has been carried out to develop inhibitors for the final two enzymes adenylosuccinate synthase and adenylosuccinate lyase. Investigators have also looked into the possibility of developing antimalarial agents that will block the de novo synthesis of pyrimidines and pyrimidine nucleotides. The greatest level of interest has been in finding inhibitors against orotidine 5’-monophosphate decarboxylase. There has also been interest in blocking deoxyuridine triphosphate nucleotidohydrolase as it plays an important role in controlling levels of dUTP in the parasite cell.