LAUSR

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 (N1‐((3,5‐dimethylbenzyl)oxy)‐N4‐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 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.