Design and synthesis of Inhibitors of PfDHODH: Towards a new treatment for malaria (360G-Wellcome-202071_Z_16_Z)

An estimated 3.3 billion people are at risk of malaria, with populations living in sub-Saharan Africa having the highest infection rates, resulting in ~219 million documented cases of malaria and in excess of 660,000 deaths in 2010. The treatment and control of malaria is increasingly difficult due to the spread of resistance to antimalarial drugs. This is a concern even for artemisinin-based combination therapies (ACTs)- the first-line of treatment, where there is evidence of altered parasite sensitivity in a number of countries. In order to eradicate malaria it is clear we will need new classes of antimalarial with novel mechanisms of action and defined pharmacological profile. It is reassuring that several potential drugs are entering clinical trials but their success or longevity is unknown, necessitating development of new inhibitors operating on novel targets. Work at Leeds and elsewhere has identified the enzyme DHODH as an attractive target for the development of new antimalarial drugs. This project will apply structure-based drug design and synthesis to produce drug-like DHODH inhibitors as potential new antimalarial drug leads, which will then be evaluated biologically.