Antimalarial activity of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors

Antimicrob Agents Chemother. 2008 Oct;52(10):3467-77. doi: 10.1128/AAC.00439-08. Epub 2008 Jul 21.


The antimalarial activity and pharmacology of a series of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors (HDACIs) was evaluated. In in vitro growth inhibition assays approximately 50 analogs were evaluated against four drug resistant strains of Plasmodium falciparum. The range of 50% inhibitory concentrations (IC(50)s) was 0.0005 to >1 microM. Five analogs exhibited IC(50)s of <3 nM, and three of these exhibited selectivity indices of >600. The most potent compound, WR301801 (YC-2-88) was shown to cause hyperacetylation of P. falciparum histones, which is a marker for HDAC inhibition in eukaryotic cells. The compound also inhibited malarial and mammalian HDAC activity in functional assays at low nanomolar concentrations. WR301801 did not exhibit cures in P. berghei-infected mice at oral doses as high as 640 mg/kg/day for 3 days or in P. falciparum-infected Aotus lemurinus lemurinus monkeys at oral doses of 32 mg/kg/day for 3 days, despite high relative bioavailability. The failure of monotherapy in mice may be due to a short half-life, since the compound was rapidly hydrolyzed to an inactive acid metabolite by loss of its hydroxamate group in vitro (half-life of 11 min in mouse microsomes) and in vivo (half-life in mice of 3.5 h after a single oral dose of 50 mg/kg). However, WR301801 exhibited cures in P. berghei-infected mice when combined at doses of 52 mg/kg/day orally with subcurative doses of chloroquine. Next-generation HDACIs with greater metabolic stability than WR301801 may be useful as antimalarials if combined appropriately with conventional antimalarial drugs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antimalarials / pharmacology*
  • Aotidae
  • Drug Resistance
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors*
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / pharmacokinetics
  • Hydroxamic Acids / pharmacology
  • In Vitro Techniques
  • Malaria / drug therapy
  • Malaria, Falciparum / drug therapy
  • Male
  • Mice
  • Mice, Inbred ICR
  • Plasmodium / drug effects*
  • Plasmodium berghei / drug effects
  • Plasmodium falciparum / drug effects
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology


  • Antimalarials
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Thiazoles