Design and Synthesis of Terephthalic Acid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Anti‐Plasmodium Activity

摘要: In this work we aimed to develop parasite-selective histone deacetylase inhibitors (HDAC) with activity against the disease-causing asexual blood stages of Plasmodium as well causal prophylactic and/or transmission blocking properties. We report design, synthesis, and biological testing a series 13 terephthalic acid-based HDAC inhibitors. All compounds showed low cytotoxicity human embryonic kidney (HEK293) cells (IC50: 8–>51 μm), 11 also having sub-micromolar in vitro drug-sensitive (3D7) multidrug-resistant (Dd2) blood-stage P. falciparum parasites (IC50≈0.1–0.5 μm). A subset were examined for early- late-stage gametocytes P. berghei exo-erythrocytic-stage parasites. While only moderate was observed (IC50>2 μm), most active compound (N1-((3,5-dimethylbenzyl)oxy)-N4-hydroxyterephthalamide, 1 f) exo-erythrocytic (IC50 0.18 μm) >270-fold better forms than HepG2 cells. This, together asexual-stage potency (IC50≈0.1 μm) selectivity versus (SI>450), suggests that 1 f may be valuable starting point development novel antimalarial drug leads host cell toxicity multi-stage anti-plasmodial activity.