New drugs for visceral leishmaniasis are urgently required as existing drugs have serious shortcomings including toxicity and drug resistance. This disease is caused by parasites from the Leishmania family which live inside human cells. Screening large collections of chemicals (>100,000) to identify compounds that kill parasites has been used to identify new start points for drug discovery. It is complex and expensive to look at such numbers using intracellular parasites. To circumvent this, many groups screen using parasites adapted to grow outside human cells (axenic forms). However, the established protocols identify growth slowing compounds as well as compounds that kill parasites. Cytocidal compounds are better start points for drug discovery. Here we present a screening cascade based on a modified axenic Leishmania assay – referred as the cidal axenic assay – adapted to identify compounds that kill parasites. We show that these compounds have a higher probability of being active against intracellular parasites. This new screening cascade was used to screen a compound collection named the Diversity Oriented Synthesis (DOS) Informer Set (9,907 compounds) and led to the identification of two new chemical series with antileishmanial activity. Their activity was confirmed against Leishmania donovani intracellular amastigote parasites. They are potential candidates for further drug development. The approach we have taken may have broad relevance to anti-infective and anti-parasitic drug discovery.

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