title: Discovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages.
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.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Finn K
authors.initials: FK
authors.lastname: Hansen
authors.affiliation: Eskitis Institute for Drug Discovery, Don Young Road, Nathan Campus, Griffith University, QLD 4111, Australia.
authors.forename: Subathdrage D M
authors.initials: SD
authors.lastname: Sumanadasa
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Stenzel
authors.affiliation: Eskitis Institute for Drug Discovery, Don Young Road, Nathan Campus, Griffith University, QLD 4111, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Duffy
authors.affiliation: Department of Pediatrics, University of California, San Diego, School of Medicine, 9500 Gilman Drive 0741, La Jolla, CA 92093, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Meister
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Marek
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Rebekka
authors.initials: R
authors.lastname: Schmetter
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Krystina
authors.initials: K
authors.lastname: Kuna
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hamacher
authors.affiliation: Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Wilhelmstr. 27, 72074 Tübingen, Germany; Medical Research Laboratory, Albert Schweitzer Hospital, Lambaréné, Gabon.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mordmüller
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
authors.affiliation: Department of Pediatrics, University of California, San Diego, School of Medicine, 9500 Gilman Drive 0741, La Jolla, CA 92093, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
authors.affiliation: Eskitis Institute for Drug Discovery, Don Young Road, Nathan Campus, Griffith University, QLD 4111, Australia.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: Eskitis Institute for Drug Discovery, Don Young Road, Nathan Campus, Griffith University, QLD 4111, Australia. Electronic address: k.andrews@griffith.edu.au.
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Andrews
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany. Electronic address: Thomas.kurz@uni-duesseldorf.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kurz
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; C400300:HDAC4 protein, human; C404500:HDAC5 protein, human; D006655:Histone Deacetylases
keywords: Asexual blood stages; Gametocyte stages; Histone deacetylase inhibitor; Liver stages; Malaria