Antimalarial activity of tetrahydro-β-carbolines targeting the ATP binding pocket of the Plasmodium falciparum heat shock 90 protein

[Display omitted] •The natural product harmine is known to have antimalarial activity.•We report a new series of harmine derivatives that show improved activity.•These compounds are thought to target the heat shock 90 protein of the parasite.•Computational studies support the heat shock 90 protein binding model.•These compounds show no toxicity against a human cell line. A series of tetrahydro-β-carboline derivatives of a lead compound known to target the heat shock 90 protein of Plasmodium falciparum were synthesized and assayed for both potency against the parasite and toxicity against a human cell line. Using a rationalized structure based design strategy, a new lead compound with a potency two orders of magnitude greater than the original lead compound was found. Additional modeling of this new lead compound suggests multiple avenues to further increase potency against this target, potentially paving the path for a therapeutic with a mode of action different than any current clinical treatment.