1609983-42-7Relevant articles and documents
Synthesis, antimalarial properties, and sar studies of alkoxyurea-based HDAC inhibitors
Hansen, Finn K.,Skinner-Adams, Tina S.,Duffy, Sandra,Marek, Linda,Sumanadasa, Subathdrage D. M.,Kuna, Krystina,Held, Jana,Avery, Vicky M.,Andrews, Katherine T.,Kurz, Thomas
, p. 665 - 670 (2014/03/21)
Histone deacetylase (HDAC) inhibitors are an emerging class of potential antimalarial drugs. We investigated the antiplasmodial properties of 16 alkoxyurea-based HDAC inhibitors containing various cap and zinc binding groups (ZBGs). Ten compounds displayed sub-micromolar activity against the 3D7 line of Plasmodium falciparum. Structure-activity relationship studies revealed that a hydroxamic acid ZBG is crucial for antiplasmodial activity, and that the introduction of bulky alkyl substituents to cap groups increases potency against asexual blood-stage parasites. We also demonstrate that selected compounds cause hyperacetylation of P.a falciparum histone H4, indicating inhibition of one or more PfHDACs. To assess the selectivity of alkoxyurea-based HDAC inhibitors for parasite over normal mammalian cells, the cytotoxicity of representative compounds was evaluated against neonatal foreskin fibroblast (NFF) cells. The most active compound, 6-((3-(4-(tert-butyl)phenyl)ureido)oxy)- N-hydroxyhexanamide (1 e, Pf3D7 IC50: 0.16a μM) was 31-fold more toxic against the asexual blood stages than towards normal mammalian cells. Moreover, a subset of four structurally diverse HDAC inhibitors revealed moderate activity against late-stage (IV-V) gametocytes.
