Exploration of fluorinated peptoid-based histone deacetylase inhibitors as dual-stage antiplasmodial agents

this study, we investigated the antiplasmodial properties of a series of fluorinated peptoid-capped histone deacetylase inhibitors (HDACi) against 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 pronounced efficacy against P. berghei liver stages (IC₅₀: 0.74 μM), while lacking activity against mature gametocytes. Compound 1j was identified as a second hit compound with slightly lower activity against asexual blood and liver stages (Pf 3D7 IC50: 0.015 μM; Pf Dd2 IC50: 0.018 μM; Pb EEF IC50: 3.69 μM) but showed excellent parasite selectivity (SIHepG2/3D7: 2053; SIHepG2/Dd2: 1711) and notable activity against mature gametocytes (IC50: 1.92 μM). Compared to our previous hit compound MAHA-022, both 1h and 1j exhibited improved activity against asexual blood stages and enhanced parasite selectivity, albeit with reduced efficacy against liver stage parasites. Taken together, compounds 1h and 1j represent promising multi-stage antiplasmodial HDACi scaffolds for further development and optimization.