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

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 (SI^HepG2/3D7: 2389; SI^HepG2/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.