Antimalarial histone deacetylase inhibitors containing cinnamate or NSAID components.
Basic Information
ID: ALA1287677
Journal: Bioorg Med Chem Lett
Title: Antimalarial histone deacetylase inhibitors containing cinnamate or NSAID components.
Authors: Wheatley NC, Andrews KT, Tran TL, Lucke AJ, Reid RC, Fairlie DP.
Abstract: 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.
CiteXplore: 20951583
DOI: 10.1016/j.bmcl.2010.09.096
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