Malaria
remains one of the most deadly infectious diseases, causing
hundreds of thousands of deaths each year, primarily in young children
and pregnant mothers. Here, we report the discovery and derivatization
of a series of pyrazolo[3,4-b]pyridines targeting Plasmodium falciparum, the deadliest species of the
malaria parasite. Hit compounds in this series display sub-micromolar in vitro activity against the intraerythrocytic stage of
the parasite as well as little to no toxicity against the human fibroblast
BJ and liver HepG2 cell lines. In addition, our hit compounds show
good activity against the liver stage of the parasite but little activity
against the gametocyte stage. Parasitological profiles, including
rate of killing, docking, and molecular dynamics studies, suggest
that our compounds may target the Qo binding site of cytochrome bc
1.
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