Malaria remains one of the most deadly infectious diseases on the planet. A recent report by the World Health Organization estimated that nearly half of the world's population is at risk of contracting the disease. In 2013 alone, there were an estimated 198 million cases of malaria resulting in 584,000 deaths with the majority of these deaths occurring in children under the age of 5. Drug resistant strains of malaria are primarily responsible for the continued death toll, as the parasite has developed resistance to several drug classes. Although antimalarial medicines such as chloroquinine have been used effectively for more than 50 years, the failure to completely wipe out malaria in the 20th century was due in large part to the parasite evolving resistance to these standard treatments. Today, artemisinin combination therapy remains a highly effective treatment for many drug-resistant cases, but emerging resistance to artemisinin has been reported for several years now. The further spread of artemisinin resistant strains now threatens modern efforts to eliminate the parasite. New antimalarial drugs that are inexpensive and efficacious are a crucial component of any strategy to eliminate the parasite. Moreover, given the ability of the parasite to develop resistance to antimalarials, highly conserved protein targets with a high fitness cost to resistance conferring mutations are high priority targets. We report the progress towards the synthesis of anti-malarials targeting the Plasmodium falciparum ATP4 protein, which is thought to be a cation transporting ATPase responsible for regulating intracellular sodium levels in the parasite. Based on preliminary screening results, we have proposed a library of more than 50 potential inhibitors. Development of our current methodology will be presented, as well as synthetic progress to date.

Synthesis of anti-malarial compounds targeting the ATP4 protein in Plasmodium falciparum

253rd National Meeting (2017)

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