Synthesis, antimalarial properties, and SAR studies of alkoxyurea-based HDAC inhibitors.
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 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 : 0.16 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.
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf (Germany).
Finn K
FK
Hansen
Tina S
TS
Skinner-Adams
Sandra
S
Duffy
Linda
L
Marek
Subathdrage D M
SD
Sumanadasa
Krystina
K
Kuna
Jana
J
Held
Vicky M
VM
Avery
Katherine T
KT
Andrews
Thomas
T
Kurz
D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D000962:Antimalarials; D056572:Histone Deacetylase Inhibitors; D014508:Urea
Plasmodium falciparum; gametocytocides; histone deacetylases; inhibitors; malaria