RESUMEN
A collection of ß-carbolines based on the natural product harmine, a compound known to target the heat shock 90 protein of Plasmodium falciparum, was synthesized and tested for antimalarial activity and potential toxicity. Several of these novel compounds display promising bioactivity, providing a new potential therapeutic with a mode of action that differs versus any currently available clinical treatment.
Asunto(s)
Antimaláricos , Antimaláricos/farmacología , Plasmodium falciparum , Carbolinas/farmacología , Respuesta al Choque TérmicoRESUMEN
A series of tetrahydro-ß-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.
Asunto(s)
Adenosina Trifosfato/química , Antimaláricos/farmacología , Carbolinas/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/síntesis química , Antimaláricos/química , Sitios de Unión/efectos de los fármacos , Carbolinas/síntesis química , Carbolinas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Plasmodium falciparum/química , Plasmodium falciparum/citología , Relación Estructura-ActividadRESUMEN
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 bc1.