Malaria is one of the most threatening diseases worldwide with approximately one third of the world's population at risk and mortality estimated at 780,000 deaths per year.  Since an effective vaccination is not yet available, small-molecule-based medicines are currently the best options for treating patients suffering from malaria.  However, given the emergence of resistance against existing medicines, there is a pressing need for the discovery of new classes of compounds not related to existing pharmacophores, but with unique cores that are more likely to have novel mechanisms of action.  We have reported the preparation of a screening collection of 100,000 diverse small molecules using a diversity oriented synthesis (DOS) strategy. The DOS compounds combine the complexity of natural products and the efficiency of high-throughput synthesis.  This library of compounds was screened in a blood stage phenotypic assay against the multi-drug resistant Dd2 Plasmodium falciparum strain.  Screening and triaging strategies to maximize the potential of identifying anti-malarials with novel mechanisms of action as well as medicinal chemistry optimization efforts will be discussed.

Development of antimalarial compounds with new mechanisms of action using next-generation synthesis

247th National Meeting (2014)

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