Antiparasitic pyrrolopyrimidines

Parasitic diseases, including malaria, leishmaniasis, and trypanosomiasis are amongst the most prevalent diseases world wide collectively with the poorest availability of effective drugs. Human African trypanosomiasis (HAT) has been reported to have a greater morbidity and mortality than HIV/AIDS in some locations. Parasitic disease is difficult to treat because the parasites become closely connected with the living host and it is therefore difficult to find drugs that attack only the parasite. Available drugs are few and are also toxic to humans. In laboratory experiments, we have shown that novel compounds designed and prepared in at the University of Strathclyde and University of Dundee are potentially able to fill the gap in drug availability. Our project is to optimise the effectiveness of our compounds to provide candidate drugs for full clinical development.

Parasitic diseases are amongst the most widespread and least treatable groups of diseases in the world affecting predominantly tropical countries. These diseases include not only malaria, which is well publicised, but also leishmaniasis and trypanosomiasis. The latter in its African form, human African trypanosomiasis (HAT), has in some places a greater morbidity and mortality than HIV/AIDS. Available drugs are ineffective and show little selective toxicity. A rational target with intrinsic selectivity is therefore required and such a target has been identified as the enzyme, pteridine reductase 1 (PTR1), which is only found in such parasites. Based upon an initial crystallographic study, we have designed and prepared a series of compounds (pyrrolopyrimidines) that are inhibitors of PTR1 and also lethal to Trypanosoma brucei. Our data contribute to proof of concept that such compounds are a potential viable therapy for HAT. The aim of this project is to design, synthesise, and evaluate further compounds that will lead directly to development candidates for HAT and potentially other tragic parasitic diseases.