Potent antimalarial activity of histone deacetylase inhibitor analogues

Queensland Institute of Medical Research, Herston, Queensland, Australia; Griffith Medical Research College, a joint program of Griffith University and the Queensland Institute of Medical Research, QIMR, Herston, QLD, Australia; Australian Centre for International and Tropical Health and Nutrition; Institute of Molecular Bioscience, University of Queensland, Queensland, Australia; School of Medicine, Central Medical Division, University of Queensland, Queensland, Australia

^* To whom correspondence should be addressed. Email: kathy.andrews{at}qimr.edu.au.

	Abstract

The malaria parasite Plasmodium falciparum has at least five putative histone deacetylase enzymes (PfHDACs) 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 histone deacetylases (hHDACs). Fourteen new compounds derived from L-cysteine, or 2-aminosuberic acid, were designed to inhibit PfHDAC-1 based on homology modeling with human class I and II HDAC enzymes. The compounds displayed highly potent anti-proliferative activity against drug resistant (Dd2) or drug sensitive (3D7) strains of P. falciparum in vitro (IC₅₀ 3-334 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 promising targets for new antimalarial drugs.