Inhibition of Plasmodium falciparum intraerythrocytic cycle by purine analogs

The purine synthesis pathways are essential for the life cycle of many pathogenic organisms in mammals. Most parasites lack the necessary enzymes for de novo synthesis of purines, using instead the salvage pathways as their only source of these substrates. The transporters and enzymes involved in the salvage pathways are considered suitable targets for chemotherapy agents and purine analogs, which are used extensively in the treatment of several diseases. The enzymes catalyzing the cleavage of glycosidic bonds of nucleosides have an essential role in the purine salvage pathway of Plasmodium spp., the parasites causing malaria, and consequently can be considered as potential therapeutic targets to design antimalarial drugs. New inhibitors of the plasmodial adenosine deaminase (PfADA), purine nucleoside phosphorylase (PfPNP) and hypoxantine-guanosine-xantine phosphoribosyl transferase (PfHGXPRT) are currently investigated for this purpose. In addition, PfPNP activity can be used for the activation of pro-drugs, which can be channeled through PfHGXPRT. The resulting metabolites would be toxic for the parasite, as they could be incorporated to RNA/DNA hampering transcription/translation or replication. In this work several purine base and purine ribonucleoside analogs displaying substitutions at positions 6, 7 and 8, and chemotherapy agents with substitutions at position 2 of adenine have been tested as potential inhibitors of the intraerythrocytic cycle of Plasmodium falciparum. Our results show that fluorinated derivatives of adenine, adenosine and adenosine phosphate inhibit intraerythrocytic P. falciparum growth at sub-cytotoxic concentrations.