Synthesis, structure-activity relationships, cocrystallization and cellular characterization of novel smHDAC8 inhibitors for the treatment of schistosomiasis
| Autor: | Ghazy, Ehab, Heimburg, Tino, Lancelot, Julien, Zeyen, Patrik, Schmidtkunz, Karin, Truhn, Anne, Darwish, Salma, Simoben, Conrad, Shaik, Tajith, Erdmann, Frank, Schmidt, Matthias, Robaa, Dina, Romier, Christophe, Jung, Manfred, Pierce, Raymond, Pierce, Ray, Sippl, Wolfgang |
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| Přispěvatelé: | Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA) |
| Rok vydání: | 2021 |
| Předmět: |
Drug
Models Molecular media_common.quotation_subject Adult worm Schistosomiasis [CHIM.THER]Chemical Sciences/Medicinal Chemistry Crystallography X-Ray 01 natural sciences Egg laying Histone Deacetylases 03 medical and health sciences Structure-Activity Relationship Docking (dog) Drug Discovery medicine Animals Humans 030304 developmental biology media_common Pharmacology 0303 health sciences biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry HDAC8 General Medicine Schistosoma mansoni biology.organism_classification medicine.disease Recombinant Proteins 0104 chemical sciences 3. Good health Praziquantel Histone Deacetylase Inhibitors HEK293 Cells Biochemistry medicine.drug |
| Zdroj: | European Journal of Medicinal Chemistry European Journal of Medicinal Chemistry, Elsevier, 2021, 225, pp.113745. ⟨10.1016/j.ejmech.2021.113745⟩ |
| ISSN: | 1768-3254 0223-5234 |
| Popis: | International audience; Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, we chemically optimized our previously reported benzhydroxamate-based inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by the highly potent inhibitor 5o. Structure-based optimization of the novel inhibitors was carried out using the available crystal structures as well as docking studies on smHDAC8. The compounds were evaluated in screens for inhibitory activity against schistosome and human HDACs (hHDAC). The in vitro and docking results were used for detailed structure activity relationships. The synthesized compounds were further investigated for their lethality against the schistosome larval stage using a fluorescence-based assay. The most promising inhibitor 5o showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture. |
| Databáze: | OpenAIRE |
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