title: Antimalarial activity of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors.
abstract: 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.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, MD 20910, USA. Geoffrey.Dow@amedd.army.mil
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Dow
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Chen
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Andrews
authors.forename: Diana
authors.initials: D
authors.lastname: Caridha
authors.forename: Lucia
authors.initials: L
authors.lastname: Gerena
authors.forename: Montip
authors.initials: M
authors.lastname: Gettayacamin
authors.forename: Jacob
authors.initials: J
authors.lastname: Johnson
authors.forename: Qigui
authors.initials: Q
authors.lastname: Li
authors.forename: Victor
authors.initials: V
authors.lastname: Melendez
authors.forename: Nicanor
authors.initials: N
authors.lastname: Obaldia
authors.forename: Thanh N
authors.initials: TN
authors.lastname: Tran
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D016645:Aotidae; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D008288:Malaria / Q000188:drug therapy; D016778:Malaria, Falciparum / Q000188:drug therapy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010961:Plasmodium / Q000187:drug effects*; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013844:Thiazoles