Histone Deacetylase Inhibitors in Antimalarial Therapeutics

Histone deacetylase (HDAC) inhibitors represent a promising class of antimalarial agents by targeting the epigenetic machinery of Plasmodium species. By blocking HDAC activity, these compounds induce hyperacetylation of histones, leading to widespread disruption of parasite gene expression and cell cycle progression. Several chemical scaffolds—such as hydroxamates, peptoids and diphenylureas—have delivered potent inhibitors active against blood-stage parasites, liver schizonts and gametocytes, with some showing efficacy against multidrug-resistant strains. The global significance of these agents lies in their novel mode of action, which complements existing therapies and offers pathways to curb transmission and counteract emerging resistance. Challenges remain in achieving selectivity over human HDAC isoforms, optimising pharmacokinetic profiles and ensuring safety in diverse patient populations. Recent advances have refined lead structures to balance potency, metabolic stability and host-cell tolerance, laying the groundwork for future clinical translation.

Research from Nature Portfolio

One study introduced a series of 1,3-diphenylureido hydroxamate inhibitors exhibiting sub-micromolar activity against both drug-sensitive and multidrug-resistant Plasmodium falciparum strains, while demonstrating marked selectivity over human HDAC1. Structure–activity relationships pinpointed an optimal phenyl linker length that facilitates high-affinity engagement with the parasite enzyme and minimises off-target effects. A parallel investigation evaluated peptoid-based HDAC6 inhibitors against clinical isolates from adults and children, reporting nanomolar IC50 values superior to those of established reference compounds across diverse genetic backgrounds. These findings underscore the feasibility of crafting parasite-selective inhibitors with favourable safety profiles for paediatric and adult use.

Histone Deacetylase Inhibitors in Antimalarial Therapeutics publication trend

The graph below shows the total number of articles in histone deacetylase inhibitors in antimalarial therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Histone deacetylase (HDAC): Enzyme that removes acetyl groups from histone tails, condensing chromatin and repressing gene transcription.

Epigenetics: Study of heritable changes in gene activity caused by mechanisms other than alterations in the DNA sequence, notably through histone and DNA chemical modifications.

IC50: Concentration of an inhibitor required to reduce a biological activity by 50%, commonly used to quantify compound potency.

Peptoid: Oligomer similar to peptides but with side chains attached to backbone nitrogen atoms, offering improved stability and modifiable pharmacokinetics.

Multistage activity: Ability of a compound to act against multiple developmental stages of the malaria parasite, including erythrocytic, hepatic and gametocyte phases.

References

1. Development of peptoid-based heteroaryl-decorated histone deacetylase (HDAC) inhibitors with dual-stage antiplasmodial activity. European Journal of Medicinal Chemistry (2024).
2. PfHDAC1 is an essential regulator of P. falciparum asexual proliferation and host cell invasion genes with a dynamic genomic occupancy responsive to artemisinin stress. mBio (2024).
3. 1,3-Diphenylureido hydroxamate as a promising scaffold for generation of potent antimalarial histone deacetylase inhibitors. Scientific Reports (2023).
4. A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1. Cell Discovery (2020).