Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 20, Issue 23, Pages 7080-7084Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.09.096
Keywords
HDAC inhibitor; Plasmodium falciparum; NSAID; Malaria; Histone
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Funding
- Australian Research Council (ARC)
- Australian National Health and Medical Research Council (NHMRC) [569735]
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Malaria is the most lethal parasite-mediated tropical infectious disease, killing 1-2 million people each year. An emerging drug target is the enzyme Plasmodium falciparum histone deacetylase 1 (PfHDAC1). We report 26 compounds designed to bind the zinc and exterior surface around the entrance to the active site of PfHDAC1, 16 displaying potent in vitro antimalarial activity (IC(50) < 100 nM) against P. falciparum. Selected compounds were shown to cause hyperacetylation of P. falciparum histones and be > 10-fold more cytotoxic towards P. falciparum than a normal human cell type (NFF). Twenty-two inhibitors feature cinnamic acid derivatives or non-steroidal anti-inflammatory drugs (NSAIDs) as HDAC-binding components. A homology model of PfHDAC1 enzyme gives new insights to interactions likely made by some of these inhibitors. Results support PfHDAC1 as a promising new antimalarial drug target. (C) 2010 Elsevier Ltd. All rights reserved.
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