期刊
CHEMMEDCHEM
卷 9, 期 3, 页码 665-670出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201300469
关键词
gametocytocides; histone deacetylases; inhibitors; malaria; Plasmodium falciparum
资金
- Deutsche Forschungsgemeinschaft (DFG)
- Australian Research Council [FT0991213, LP120200557]
- Australian Research Council [FT0991213] Funding Source: Australian Research Council
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 (1e, Pf3D7 IC50: 0.16M) 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.
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