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Design and Synthesis of Terephthalic Acid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Anti‐ Plasmodium Activity
Author(s) -
Stenzel Katharina,
Chua Ming Jang,
Duffy Sandra,
AntonovaKoch Yevgeniya,
Meister Stephan,
Hamacher Alexandra,
Kassack Matthias U.,
Winzeler Elizabeth,
Avery Vicky M.,
Kurz Thomas,
Andrews Katherine T.,
Hansen Finn K.
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700360
Subject(s) - gametocyte , plasmodium falciparum , histone deacetylase , plasmodium berghei , ic50 , biology , cytotoxicity , pharmacology , in vitro , in vivo , biochemistry , chemistry , malaria , histone , immunology , gene , microbiology and biotechnology
In this work we aimed to develop parasite‐selective histone deacetylase inhibitors (HDAC) inhibitors with activity against the disease‐causing asexual blood stages of Plasmodium as well as causal prophylactic and/or transmission blocking properties. We report the design, synthesis, and biological testing of a series of 13 terephthalic acid‐based HDAC inhibitors. All compounds showed low cytotoxicity against human embryonic kidney (HEK293) cells (IC 50 : 8–>51 μ m ), with 11 also having sub‐micromolar in vitro activity against drug‐sensitive (3D7) and multidrug‐resistant (Dd2) asexual blood‐stage P. falciparum parasites (IC 50 ≈0.1–0.5 μ m ). A subset of compounds were examined for activity against early‐ and late‐stage P. falciparum gametocytes and P. berghei exo‐erythrocytic‐stage parasites. While only moderate activity was observed against gametocytes (IC 50 >2 μ m ), the most active compound ( N 1 ‐((3,5‐dimethylbenzyl)oxy)‐ N 4 ‐hydroxyterephthalamide, 1 f ) showed sub‐micromolar activity against P. berghei exo‐erythrocytic stages (IC 50 0.18 μ m ) and >270‐fold better activity for exo‐erythrocytic forms than for HepG2 cells. This, together with asexual‐stage in vitro potency (IC 50 ≈0.1 μ m ) and selectivity of this compound versus human cells (SI>450), suggests that 1 f may be a valuable starting point for the development of novel antimalarial drug leads with low host cell toxicity and multi‐stage anti‐plasmodial activity.