ANTI-PARASITIC PYRROLOPYRIMIDINES

Project: Research

Description

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.

Key findings

New experimental drugs for the treatment of trypanosomiasis (sleeping sickness) were synthesised with the specific enzyme, pteridine reductase 1 from Trypanosoma brucei (the sleeping sickness parasite) as the target. Several effective enzyme inhibitors were prepared and their detailed interactions at the atomic level probed by X-ray crystallography, which gave a clear understanding of the structures required for activity. The best compounds were profiled further for physicochemical properties and a small number finally evaluated in an in vivo mouse model of stage 1 trypanosomiasis. While two molecules were found to provide a cure, both were found to be too toxic for further development as drugs to treat human disease. However the study validated the enzyme as a target for drugs to treat trypanosomiasis and defined some important requirements and limitations for potentially active compounds that could be synthesised and subsequently developed.
StatusFinished
Effective start/end date1/10/1031/12/13

Funding

  • Medical Research Council: £25,050.00
  • Medical Research Council: £317,277.00

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Trypanosomiasis
Pharmaceutical Preparations
Parasitic Diseases
Parasites
Poisons
African Trypanosomiasis
Trypanosoma brucei brucei
Leishmaniasis
pyrrolopyrimidine
X Ray Crystallography
Enzyme Inhibitors
Enzymes
Malaria
Acquired Immunodeficiency Syndrome
HIV
Morbidity
Mortality