Synthesis, Crystallization Studies, and in vitro Characterization of Cinnamic Acid Derivatives as Sm HDAC8 Inhibitors for the Treatment of Schistosomiasis
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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 deacetylase 8 (Sm HDAC8). The crystal structures of Sm HDAC8 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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smHDAC8 crystals can be used to look at inhibitor binding in a crystal lattice-unbiased manner.
“We have previously shown that our smHDAC8 crystals can be used to look at inhibitor binding in a crystal latticeunbiased manner 29, 30, 55-58 .”
From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [55]
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- Authors
- Bayer, T., Chakrabarti, A., Lancelot, J., Shaik, T. B., Hausmann, K., Melesina, J., Schmidtkunz, K., Marek, M., Erdmann, F., Schmidt, M., Robaa, D., Romier, C., Pierce, R. J., Jung, M., & Sippl, W.
- Affiliations
- Martin Luther University Halle-Wittenberg (DE)
- University of Freiburg (DE)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Sippl, Wolfgang
- ORCID
- Venue
- ChemMedChem
- Publisher
- Wiley
- Published
- 2018-07-04
- Volume
- 13
- Issue
- 15
- Pages
- 1517-1529
- ISSN
- 1860-7179 (ISSN-L)
- 1860-7187
- OpenAlex
- W2806343349
- Cited by
- 23
- References
- 38
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 5 · 2020: 6 · 2019: 2 · 2018: 2
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- green
- hal.science
- Licence
- Locations
- ChemMedChem (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Seventh Framework Programme (602080)
- Deutsche Forschungsgemeinschaft (Ju 295/13-1, Si 846/13-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Immunology and Microbiology › Parasitology › Parasites and Host Interactions
- Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
- Keywords
- schistosomiasis, Schistosoma mansoni, HDAC8, HDAC8 inhibitors, cinnamic acid derivatives, hydroxamic acids, praziquantel alternatives, crystal structure, binding mode, oviposition, neglected parasitic diseases
- MeSH terms
- Animals, Cinnamates, Crystallization, Histone Deacetylases, Protein Conformation, Schistosoma mansoni, Schistosomiasis, Structure-Activity Relationship, Crystallography, X-Ray, Histone Deacetylase Inhibitors, Molecular Docking Simulation, In Vitro Techniques
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