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

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Hansen, Finn K
Sumanadasa, Subathdrage DM
Stenzel, Katharina
Duffy, Sandra
Meister, Stephan
Marek, Linda
Schmetter, Rebekka
Kuna, Krystina
Hamacher, Alexandra
Mordmueller, Benjamin
Kassack, Matthias U
Winzeler, Elizabeth A
Avery, Vicky M
Andrews, Katherine T
Kurz, Thomas
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2014
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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.

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European Journal of Medicinal Chemistry

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82

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Medicinal and biomolecular chemistry

Medicinal and biomolecular chemistry not elsewhere classified

Organic chemistry

Pharmacology and pharmaceutical sciences

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