1,3-diphenylureido hydroxamate: a promising scaffold for generation of potent antimalarial histone deacetylase inhibitors

We report a series of 1,3-diphenylureido hydroxamate HDAC inhibitors evaluated against sensitive and drug-resistant P. falciparum strains. Compounds 8a-d show potent antiplasmodial activity, indicating that a phenyl spacer allows improved potency relative to cinnamyl and di-hydrocinnamyl linkers. In vitro , mechanistic studies demonstrated target activity for Pf HDAC1 on a recombinant level, which agreed with cell quantification of the acetylated histone levels. In silico studies suggest that the phenyl linker has an ideal length in the series for permitting effective interactions of the hydroxamate with Pf HDAC1 and that this compound series could bind as well as in Hs HDAC1. Taken together, these results highlight the potential of diphenylurea hydroxamates as a privileged scaffold for the generation of potent antimalarial HDAC inhibitors with improved selectivity over human HDACs.