Nucleobase derivatives as drugs against trypanosomal diseases
Keywords: Trypanosomatidae, drugs
Leishmaniasis, African trypanosomiasis and Chagas' disease are neglected diseases responsible for substantial global morbidity, mortality, and economic adversity, and in most countries, existing strategies for control and treatment are either failing or under serious threat. New tools for combating pathogenic protozoa and the development and exploitation of new drug targets are required. The main objective is the identification of novel compounds for the treatment of the leishmaniases and trypanosomiases. A two-pronged approach is proposed to discover leads for the treatment of these diseases by targeting nucleoside/ nucleotide metabolism. 1) A phenotypic approach exploring the potential of large collections of novel nucleobase derivatives against parasites. 2) A target-based approach specifically centred on the development of inhibitors of the enzyme deoxyuridine triphosphate nucleotidohydrolase.
Trypanosomatid neglected diseases are mainly confined to tropical and sub-tropical regions, particularly affecting the third world, although visitors to endemic countries are also at risk. The leishmaniases threaten about 350 million people, giving rise to around 2 million clinical cases each year of which about 25% are due to the fatal disease visceral leishmaniasis. Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense cause African trypanosomaisis, with epidemics raging in a number of countries in sub-Saharan Africa, causing an estimated 50,000 cases annually. Trypanosoma cruzi causes Chagas’ disease; currently 16-18 million people are infected with about 100 million at risk from the disease. Vaccine development is problematic for these diseases although in some cases, vector control has been effective in reducing the incidence. Chemotherapy remains the major means for control however the current therapeutic agents are unsatisfactory. There are many reported cases of resistance and the available drugs show lack of clinical effectiveness and side effects.
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The aim is to identify compounds that have potent antiparasitic activity and have drug-like properties.
The main expected outcome of the project will be the identification of nucleobase derivatives exhibiting potent activity against protozoa of the Trypanosomatidae family and that present "drug-like" properties that will make them amenable to clinical development.
Emerging compounds and knowledge can be used in the further development of drugs that fulfil the requirements concerning suitability for use in developing countries.