• Sintesi e valutazione biologica di inibitori di ad

Adenosine deaminase (ADA) in humans deaminates adenosine and deoxyadenosine to form the respective inosines and thereby plays an essential role in purine metabolism. Adenosine deaminase is also important in purine salvage pathways in microorganisms and is thought to be essential for salvage pathways in purine auxotrophs like Plasmodium falciparum.1,2 The adenosine deaminase inhibitors coformycin and 2′-deoxycoformycin (also known as Pentostatin) are natural product transition state analogue inhibitors that bind with picomolar affinity to adenosine deaminases. Inhibition of adenosine deaminase results in the accumulation of adenosine and deoxyadenosine. Recently, the ADA from P. falciparum (PfADA) has been characterized and found to catalyze the deamination of adenosine. Inhibition of the purine salvage pathway with plasmodium ADA inhibitors is lethal for P. falciparum in vitro.3
Malaria is caused by protozoan parasites of the Plasmodium genus. Malaria treatment by chemotherapeutic and vector control strategies have not prevented its widespread occurrence.
Selective inhibition of ADA Plasmodium represents therefore a challenging therapeutic strategy in the treatment of malaria which is becoming more and more endemic, due to deforestation, population migration and changes in agricultural practice. Urban malaria is becoming an increasing problem in many countries.
In my thesis work I synthesized and tested new potential antimalarial drugs with a pyrazolopyrimidine core, able to selectively inhibit Plasmodium adenosine deaminase.