Antimalarial histone deacetylase inhibitors containing cinnamate or NSAID components.
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.
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia.
Nicole C
NC
Wheatley
Katherine T
KT
Andrews
Truc L
TL
Tran
Andrew J
AJ
Lucke
Robert C
RC
Reid
David P
DP
Fairlie
D000107:Acetylation / Q000187:drug effects; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002934:Cinnamates / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000962:Antimalarials; D002934:Cinnamates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors