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Antimicrobial Agents and Chemotherapy, April 2008, p. 1454-1461, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.00757-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues ^,

K. T. Andrews,^1,2,3*, T. N. Tran,^1,2, A. J. Lucke,⁴ P. Kahnberg,⁴ G. T. Le,⁴ G. M. Boyle,¹ D. L. Gardiner,¹ T. S. Skinner-Adams,^1,5 and D. P. Fairlie^4*

Queensland Institute of Medical Research, Herston, Queensland, Australia,¹ Griffith Medical Research College, Joint Program of Griffith University and the Queensland Institute of Medical Research, Herston, Queensland, Australia,² Australian Centre for International and Tropical Health and Nutrition, University of Queensland, Queensland, Australia,³ Institute of Molecular Bioscience, University of Queensland, Queensland, Australia,⁴ School of Medicine, Central Medical Division, University of Queensland, Queensland, Australia⁵

Received 11 June 2007/ Returned for modification 25 September 2007/ Accepted 12 January 2008

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.

Published ahead of print on 22 January 2008.

Supplemental material for this article may be found at http://aac.asm.org/.

K.T.A. and T.N.T. contributed equally to the manuscript.

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