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

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 (IC : 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 (IC ≈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 (IC >2 μm), the most active compound (N -((3,5-dimethylbenzyl)oxy)-N -hydroxyterephthalamide, 1 f) showed sub-micromolar activity against P. berghei exo-erythrocytic stages (IC 0.18 μm) and >270-fold better activity for exo-erythrocytic forms than for HepG2 cells. This, together with asexual-stage in vitro potency (IC ≈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.

Structure–Activity and Structure–Toxicity Relationships of Peptoid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Antiplasmodial Activity

“…In this regard, we and others hypothesized that class‐II‐selective hHDACi might be a better starting point for the development of parasite‐selective antiplasmodial HDACi, due to their usually lower toxicity toward mammalian cells . In addition, knock‐out experiments with the class IIb isozyme hHDAC6 in mice led to a viable phenotype with no significant defects .…”

“…Children and pregnant women are the most at‐risk populations, with Plasmodium falciparum infection causing the highest mortality . Although some progress has been made in the field of malaria vaccines, vector control and antimalarial drugs continue to be the mainstays of malaria prevention and treatment . Unfortunately, the efficacy of antimalarial drugs is threatened by the development of parasite resistance, including to the current gold standard artemisinin‐based combination therapies (ACTs) .…”

“…Another interesting finding regarding antiplasmodial HDACi is their activity against several malaria parasite life‐cycle stages. While most antimalarial drugs target just one specific life‐cycle stage (mostly asexual blood stages), several HDACi are also active against liver stages and late‐stage gametocytes . This highlights the potential of HDACi as novel antiplasmodial agents.…”

Multicomponent Synthesis and Binding Mode of Imidazo[1,2-a]pyridine-Capped Selective HDAC6 Inhibitors

“…All synthesized hydroxamic acids were evaluated in regards to their inhibitory activity in a biochemical assay against HDAC1 and HDAC6 using ZMAL (Z-(Ac)Lys-AMC) 9 as a substrate, as previously published (Table 1). 10 First, the HDAC isoform profiling revealed that the majority of compounds showed potent double-digit nanomolar activity against HDAC6. In particular, the nature of substituent R 1 seems to be important for the selectivity profile.…”

Robert Foster Cherry Award: N. K. Garg / Innovation Prize in Medicinal/Pharmaceutical Chemistry: F. K. Hansen and A. Titz

“…Hansen and his research group are interested in the development of selective histone deacetylase inhibitors, C‐terminal Hsp90 inhibitors, and multi‐target drugs. He has reported in Chemistry—A European Journal on α‐aminoxy peptoids, and in ChemMedChem on histone deacetylase inhibitors …”