Identification of novel compounds with prophylactic activity against hypnozoites using a Plasmodium cynomolgi in vitro model.

This study aimed to identify new compounds with prophylactic activity against Plasmodium liver stages, particularly hypnozoites. A small, focused set of 568 compounds from the GSK open-access TCAMS library was tested in vitro against Plasmodium cynomolgi liver stages. Among these compounds, 12 showed IC50 values below 2 µM against hypnozoites, with the most active compound displaying nanomolar activity. These active compounds could be assigned to/grouped into six chemical clusters. Some compounds could be associated with potential known modes of action such as cytochrome bc1 inhibition or kinase inhibition, whereas the mode of action of other hit compounds is currently unknown. The high hit rate in this screening may be attributed to preselecting compounds based on their activity against gametocytes and liver stages in other Plasmodium species. Based on our findings, we suggest that this preselection methodology is appropriate for finding compounds that are active against hypnozoites.