Design and Synthesis of Terephthalic Acid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Anti‐Plasmodium Activity. (13th September 2017)

• Record Type: Journal Article
• Authors: Stenzel, Katharina; Chua, Ming Jang; Duffy, Sandra; Antonova‐Koch, Yevgeniya; Meister, Stephan; Hamacher, Alexandra; Kassack, Matthias U.; Winzeler, Elizabeth; Avery, Vicky M.; Kurz, Thomas; Andrews, Katherine T.; Hansen, Finn K.
• Is Part Of: ChemMedChem. Volume 12:Number 19(2017)
• Page Start: 1627
• Page End: 1636
• Publication Date: 2017-09-13
• Subjects: anti-plasmodial -- histone deacetylase -- inhibitors -- malaria -- Plasmodium falciparum; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201700360
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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 (IC50 : 8–>51 μm ), with 11 also having sub‐micromolar in vitro activity against drug‐sensitive (3D7) and multidrug‐resistant (Dd2) asexual blood‐stage P. falciparum parasites (IC50 ≈0.1–0.5 μm ). 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 (IC50 >2 μm ), 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 (IC50 0.18 μm ) and >270‐fold better activity for exo‐erythrocytic forms than for HepG2 cells. This, together with asexual‐stage in vitro potency (IC50 ≈0.1 μm ) and selectivity of this compound versus human cells (SI>450), suggests that1 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. Abstract : Potent & selective : A series of novel terephthalic acid‐based HDAC inhibitors (HDACi) were synthesized and screened for activity against different malaria parasite life‐cycle stages. Compound1 f was identified as a parasite‐selective HDACi with potent dual‐stage anti‐plasmodial activity. Compound1 f is therefore a useful starting point for further optimization toward anti‐plasmodial HDACi with high parasite‐specific activity.