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Synthesis, Antimalarial Properties, and SAR Studies of Alkoxyurea‐Based HDAC Inhibitors
Author(s) -
Hansen Finn K.,
SkinnerAdams Tina S.,
Duffy Sandra,
Marek Linda,
Sumanadasa Subathdrage D. M.,
Kuna Krystina,
Held Jana,
Avery Vicky M.,
Andrews Katherine T.,
Kurz Thomas
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300469
Subject(s) - histone deacetylase , plasmodium falciparum , hydroxamic acid , chemistry , cytotoxicity , potency , acetylation , gametocyte , biochemistry , stereochemistry , pharmacology , biology , histone , in vitro , gene , malaria , immunology
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. falciparum histone H4, indicating inhibition of one or more Pf HDACs. 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 , Pf 3D7 IC 50 : 0.16 μ M ) 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.