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

Dow, Geoffrey S., Chen, Yufeng, Andrews, Katherine T., Caridha, Diana, Gerena, Lucia, Gettayacamin, Montip, Johnson, Jacob, Li, Qigui, Melendez, Victor, Obaldia, Nicanor, Tran, Thanh N. and Kozikowski, Alan P. (2008) Antimalarial activity of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors. Antimicrobial Agents and Chemotherapy, 52 10: 3467-3477. doi:10.1128/AAC.00439-08

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Author Dow, Geoffrey S.
Chen, Yufeng
Andrews, Katherine T.
Caridha, Diana
Gerena, Lucia
Gettayacamin, Montip
Johnson, Jacob
Li, Qigui
Melendez, Victor
Obaldia, Nicanor
Tran, Thanh N.
Kozikowski, Alan P.
Title Antimalarial activity of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 0066-4804
1098-6596
Publication date 2008-10-01
Sub-type Article (original research)
DOI 10.1128/AAC.00439-08
Open Access Status File (Publisher version)
Volume 52
Issue 10
Start page 3467
End page 3477
Total pages 11
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Language eng
Formatted 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 (IC50s) was 0.0005 to >1 µM. Five analogs exhibited IC50s 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Australian Centre for International & Tropical Health
 
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Created: Thu, 03 Sep 2009, 19:32:42 EST by Mr Andrew Martlew on behalf of Australian Centre for International and Tropical Health and Nutrition