Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Aug;358(8):e70071.
doi: 10.1002/ardp.70071.

Exploration of Fluorinated Peptoid-Based Histone Deacetylase Inhibitors as Dual-Stage Antiplasmodial Agents

Nina Reßing  1 , Daniel Stopper  1 , Thomas Martin Schäfer  2 , Lais Pessanha de Carvalho  2 , Elizabeth A Winzeler  3 , Jana Held  2   4 , Finn K Hansen  1
Affiliations

Exploration of Fluorinated Peptoid-Based Histone Deacetylase Inhibitors as Dual-Stage Antiplasmodial Agents

Nina Reßing et al. Arch Pharm (Weinheim). 2025 Aug.

Abstract

The antiplasmodial properties of a series of fluorinated peptoid-capped histone deacetylase inhibitors (HDACi) were investigated against asexual blood stages of the drug-sensitive 3D7 and drug-resistant Dd2 strains of Plasmodium falciparum, as well as the exo-erythrocytic liver stages and mature gametocytes. Among the series, compound 1h emerged as the most potent derivative, showing strong activity against both P. falciparum strains (Pf 3D7 and Dd2 IC50: 0.010 μM) and Plasmodium berghei liver stages (Pb EEF IC50: 0.74 μM), while lacking activity against mature gametocytes. Compound 1b was identified as a second hit compound with slightly lower activity against asexual blood and liver stages (Pf 3D7 IC50: 0.019 μM; Pf Dd2 IC50: 0.023 μM; Pb EEF IC50: 2.25 μM) but showed excellent parasite selectivity (SIHepG2/3D7: 2389; SIHepG2/Dd2: 1973) and low single-digit micromolar activity against mature gametocytes (IC50: 1.70 μM). Compared to our previous hit compound MAHA-022, both 1b and 1h exhibited improved activity against asexual blood stages and enhanced parasite selectivity, albeit with reduced activity against liver stage parasites. Taken together, compounds 1b and 1h represent promising multi-stage antiplasmodial HDACi scaffolds for further development and optimization.

Keywords: HDAC inhibitors; epigenetics; histone deacetylase; malaria; peptoid.

PubMed Disclaimer

Similar articles

See all similar articles

References

    1. World Health Organization, World Malaria Report 2024 (World Health Organization, 2023).
    1. S. C. T. Partnership., “Efficacy and Safety of RTS,S/AS01 Malaria Vaccine With or Without a Booster Dose in Infants and Children in Africa: Final Results of a Phase 3, Individually Randomised, Controlled Trial,” Lancet 386 (2015): 31–45.
    1. P. Adepoju, “RTS,S Malaria Vaccine Pilots in Three African Countries,” Lancet 393 (2019): 1685.
    1. M. B. Laurens, “RTS,S/AS01 Vaccine (Mosquirix™): An Overview,” Human Vaccines & Immunotherapeutics 16 (2019): 480.
    1. S. C. T. Partnership, “Efficacy and Safety of RTS,S/AS01 Malaria Vaccine With or Without a Booster Dose in Infants and Children in Africa: Final Results of a Phase 3, Individually Randomised, Controlled Trial,” Lancet 386 (2015): 31–45.

MeSH terms

LinkOut - more resources