Synthesis, Crystallization Studies, and in vitro Characterization of Cinnamic Acid Derivatives as SmHDAC8 Inhibitors for the Treatment of Schistosomiasis. (4th July 2018)

• Record Type: Journal Article
• Authors: Bayer, Theresa; Chakrabarti, Alokta; Lancelot, Julien; Shaik, Tajith B.; Hausmann, Kristin; Melesina, Jelena; Schmidtkunz, Karin; Marek, Martin; Erdmann, Frank; Schmidt, Matthias; Robaa, Dina; Romier, Christophe; Pierce, Raymond J.; Jung, Manfred; Sippl, Wolfgang
• Is Part Of: ChemMedChem. Volume 13:Number 15(2018)
• Page Start: 1517
• Page End: 1529
• Publication Date: 2018-07-04
• Subjects: crystal structures -- docking -- HDAC -- hydroxamic acid -- schistosomiasis; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201800238
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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. Abstract : Hitting a firm target : A series of Schistosoma mansoni histone deacetylase 8 ( Sm HDAC8) inhibitors were developed by structure‐based design that showed promising in vitro inhibitory activity. Structure‐guided optimization on the basis of four solved crystal structures of Sm HDAC8 resulted in nanomolar inhibitors with good selectivity over the mostly expressed human HDAC1 and 6. Two compounds showed significant, dose‐dependent killing of the parasite and markedly impaired egg laying of adult worm pairs. These compounds are therefore promising candidates for in vivo studies.