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The emergence and spread of drug resistance to current antimalarial therapies remains a pressing concern, increasing the need for compounds that demonstrate new modes of action. Brussonol is an icetexane derivative that have been isolated from several terrestrial plants. Recent studies of our group demonstrated that the Brussonol showed inhibitory activities against Plasmodium falciparum in the low micromolar (IC50 = 16 μM) and fast-acting in vitro1. Here, we investigated the mode of action underlying brussonol antiplasmodial activity. A similarity-based search in SciFinder, identified the cyclopiazonic acid (CPA), a highly selective inhibitor for a P. falciparum sarco/endoplasmic reticulum Ca2+-ATPase (PfSERCA) pump2, as structural-related compound to brussonol. Thus, brussonol activity on the calcium modulation was investigated using parasites loaded with intracellular calcium indicator Fluo-4 AM. This investigation indicated that brussonol increased the cytosolic calcium levels within the parasite, however, by a different mechanism than CPA, impacting on calcium homeostasis and parasite development.
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