Description:
<jats:title>Abstract</jats:title><jats:p>In this work we aimed to develop parasite‐selective histone deacetylase inhibitors (HDAC) inhibitors with activity against the disease‐causing asexual blood stages of <jats:italic>Plasmodium</jats:italic> 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<jats:sub>50</jats:sub>: 8–>51 μ<jats:sc>m</jats:sc>), with 11 also having sub‐micromolar in vitro activity against drug‐sensitive (3D7) and multidrug‐resistant (Dd2) asexual blood‐stage <jats:italic>P. falciparum</jats:italic> parasites (IC<jats:sub>50</jats:sub>≈0.1–0.5 μ<jats:sc>m</jats:sc>). A subset of compounds were examined for activity against early‐ and late‐stage <jats:italic>P. falciparum</jats:italic> gametocytes and <jats:italic>P. berghei</jats:italic> exo‐erythrocytic‐stage parasites. While only moderate activity was observed against gametocytes (IC<jats:sub>50</jats:sub>>2 μ<jats:sc>m</jats:sc>), the most active compound (<jats:italic>N</jats:italic><jats:sup>1</jats:sup>‐((3,5‐dimethylbenzyl)oxy)‐<jats:italic>N</jats:italic><jats:sup>4</jats:sup>‐hydroxyterephthalamide, <jats:bold>1 f</jats:bold>) showed sub‐micromolar activity against <jats:italic>P. berghei</jats:italic> exo‐erythrocytic stages (IC<jats:sub>50</jats:sub> 0.18 μ<jats:sc>m</jats:sc>) and >270‐fold better activity for exo‐erythrocytic forms than for HepG2 cells. This, together with asexual‐stage in vitro potency (IC<jats:sub>50</jats:sub>≈0.1 μ<jats:sc>m</jats:sc>) and selectivity of this compound versus human cells (SI>450), suggests that <jats:bold>1 f</jats:bold> 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.</jats:p>