title: Potent antimalarial activity of histone deacetylase inhibitor analogues.
abstract: The malaria parasite Plasmodium falciparum has at least five putative histone deacetylase (HDAC) enzymes, which have been proposed as new antimalarial drug targets and may play roles in regulating gene transcription, like the better-known and more intensively studied human HDACs (hHDACs). Fourteen new compounds derived from l-cysteine or 2-aminosuberic acid were designed to inhibit P. falciparum HDAC-1 (PfHDAC-1) based on homology modeling with human class I and class II HDAC enzymes. The compounds displayed highly potent antiproliferative activity against drug-resistant (Dd2) or drug sensitive (3D7) strains of P. falciparum in vitro (50% inhibitory concentration of 13 to 334 nM). Unlike known hHDAC inhibitors, some of these new compounds were significantly more toxic to P. falciparum parasites than to mammalian cells. The compounds inhibited P. falciparum growth in erythrocytes at both the early and late stages of the parasite's life cycle and caused altered histone acetylation patterns (hyperacetylation), which is a marker of HDAC inhibition in mammalian cells. These results support PfHDAC enzymes as being promising targets for new antimalarial drugs.
authors.affiliation: Clinical Tropical Medicine Laboratory, Queensland Institute of Medical Research, PO Box Royal Brisbane Hospital, Herston, Queensland 4029, Australia. kathy.andrews@qimr.edu.au
authors.forename: K T
authors.initials: KT
authors.lastname: Andrews
authors.forename: T N
authors.initials: TN
authors.lastname: Tran
authors.forename: A J
authors.initials: AJ
authors.lastname: Lucke
authors.forename: P
authors.initials: P
authors.lastname: Kahnberg
authors.forename: G T
authors.initials: GT
authors.lastname: Le
authors.forename: G M
authors.initials: GM
authors.lastname: Boyle
authors.forename: D L
authors.initials: DL
authors.lastname: Gardiner
authors.forename: T S
authors.initials: TS
authors.lastname: Skinner-Adams
authors.forename: D P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D003545:Cysteine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004912:Erythrocytes / Q000469:parasitology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008958:Models, Molecular; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D017386:Sequence Homology, Amino Acid
chemical_list: D000600:Amino Acids, Dicarboxylic; D000962:Antimalarials; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C019146:2-aminosuberic acid; D003545:Cysteine