Journal
CHEMMEDCHEM
Volume 13, Issue 15, Pages 1517-1529Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201800238
Keywords
crystal structures; docking; HDAC; hydroxamic acid; schistosomiasis
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Funding
- European Union's Seventh Framework Program for research, technological development and demonstration [602080]
- European Regional Development Fund of the European Commission
- Deutsche Forschungsgemeinschaft (DFG) [Ju 295/13-1, Si 846/13-1]
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Schistosomiasis is a neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy relies on mass treatment with only one drug: praziquantel. Based on the 3-chlorobenzothiophene-2-hydroxamic acid J1075, a series of hydroxamic acids with different scaffolds were prepared as potential inhibitors of Schistosoma mansoni histone deacetylase8 (SmHDAC8). The crystal structures of SmHDAC8 with four inhibitors provided insight into the binding mode and orientation of molecules in the binding pocket as well as the orientation of its flexible amino acid residues. The compounds were evaluated in screens for inhibitory activity against schistosome and human HDACs. The most promising compounds were further investigated for their activity toward the major human HDAC isotypes. The most potent inhibitors were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Two of the compounds showed significant, dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.
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