Discovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages

Eur J Med Chem. 2014 Jul 23:82:204-13. doi: 10.1016/j.ejmech.2014.05.050.

Finn K Hansen ¹, Subathdrage D M Sumanadasa ², Katharina Stenzel ¹, Sandra Duffy ², Stephan Meister ³, Linda Marek ¹, Rebekka Schmetter ¹, Krystina Kuna ¹, Alexandra Hamacher ¹, Benjamin Mordmüller ⁴, Matthias U Kassack ¹, Elizabeth A Winzeler ³, Vicky M Avery ², Katherine T Andrews ⁵, Thomas Kurz ⁶

Affiliations

1 Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
2 Eskitis Institute for Drug Discovery, Don Young Road, Nathan Campus, Griffith University, QLD 4111, Australia.
3 Department of Pediatrics, University of California, San Diego, School of Medicine, 9500 Gilman Drive 0741, La Jolla, CA 92093, USA.
4 Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Wilhelmstr. 27, 72074 Tübingen, Germany; Medical Research Laboratory, Albert Schweitzer Hospital, Lambaréné, Gabon.
5 Eskitis Institute for Drug Discovery, Don Young Road, Nathan Campus, Griffith University, QLD 4111, Australia. Electronic address: k.andrews@griffith.edu.au.
6 Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany. Electronic address: Thomas.kurz@uni-duesseldorf.de.

PMID: 24904967 DOI: 10.1016/j.ejmech.2014.05.050

Abstract

In this work we investigated the antiplasmodial activity of a series of HDAC inhibitors containing an alkoxyamide connecting-unit linker region. HDAC Inhibitor 1a (LMK235), previously shown to be a novel and specific inhibitor of human HDAC4 and 5, was used as a starting point to rapidly construct a mini-library of HDAC inhibitors using a straightforward solid-phase supported synthesis. Several of these novel HDAC inhibitors were found to have potent in vitro activity against asexual stage Plasmodium falciparum malaria parasites. Representative compounds were shown to hyperacetylate P. falciparum histones and to inhibit deacetylase activity of recombinant PfHDAC1 and P. falciparum nuclear extracts. All compounds were also screened in vitro for activity against Plasmodium berghei exo-erythrocytic stages and selected compounds were further tested against late stage (IV and V) P. falciparum gametocytes. Of note, some compounds showed nanomolar activity against all three life cycle stages tested (asexual, exo-erythrocytic and gametocyte stages) and several compounds displayed significantly increased Parasite selectivity compared to the reference HDAC Inhibitor suberoylanilide hydroxamic acid (SAHA). These data suggest that it may be possible to develop HDAC inhibitors that target multiple malaria Parasite life cycle stages.

Keywords

Asexual blood stages; Gametocyte stages; Histone deacetylase inhibitor; Liver stages; Malaria.

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