In vitro effects of purine and pyrimidine analogues on Leishmania donovani and Leishmania infantum promastigotes and intracellular amastigotes

Abstract : Inhibition of parasite metabolic pathways is a rationale for new chemotherapeutic strategies. The pyrimidine and purine salvage pathways are thus targets against Leishmania donovani and L. infantum, causative agents of visceral human leishmaniasis and canine leishmaniosis. The antiproliferative effect of the pyrimidine analogues Cytarabine and 5-fluorouracil and of the purine analogues Azathioprine and 6-mercaptopurine was evaluated in vitro on the promastigote and the intracellular amastigote stages of the parasite. Cytarabine and 5-fluorouracil were the best inhibitors against promastigotes, whereas 5- fluorouracil and azathioprine displayed the best efficacy against the amastigote stage. The ultrastructural study showed an important cytoplasmic vacuolization and with azathioprine and 5-fluorouracyl, a mitochondrial swelling and appearance of autophagosome-like structures. Alterations of the kinetoplast were also observed with 5-fluorouracil, all these damages eventually resulting in an autolysis process that triggered the subsequent death of the intracellular parasites.