Design and synthesis of terephthalic acid-based histone deacetylase inhibitors with dual stage anti-Plasmodium activity.

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 mu m), with 11 also having sub-micromolar invitro activity against drug-sensitive (3D7) and multidrug-resistant (Dd2) asexual blood-stage P.falciparum parasites (IC50 approximate to 0.1-0.5 mu 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 (IC50>2 mu m), the most active compound (N-1-((3,5-dimethylbenzyl)oxy)-N-4-hydroxyterephthalamide, 1f) showed sub-micromolar activity against P.berghei exo-erythrocytic stages (IC50 0.18 mu m) and >270-fold better activity for exo-erythrocytic forms than for HepG2 cells. This, together with asexual-stage invitro potency (IC50 approximate to 0.1 mu m) and selectivity of this compound versus human cells (SI > 450), suggests that 1f 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.