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 (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.

中文翻译：

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肉桂酸衍生物作为SmHDAC8抑制剂的合成，结晶研究和体外表征，用于治疗血吸虫病

血吸虫病是一种被忽视的寄生虫病，在全世界影响超过2.65亿人，其控制策略依赖于仅用一种药物：吡喹酮进行的大规模治疗。基于3-氯苯并噻吩-2-异羟肟酸J1075，制备了一系列具有不同骨架的异羟肟酸作为曼氏血吸虫组蛋白脱乙酰基酶8（Sm HDAC8）的潜在抑制剂。Sm的晶体结构具有四种抑制剂的HDAC8提供了洞察结合口袋中分子的结合模式和方向以及其柔性氨基酸残基的方向的信息。在筛选中评估了这些化合物对血吸虫和人HDAC的抑制活性。进一步研究了最有前途的化合物对人类主要HDAC同种型的活性。此外，还使用基于荧光的分析方法对最有效的抑制剂针对血吸虫幼虫期的致死性进行了筛选。其中两种化合物显示出对血吸虫的幼虫具有明显的剂量依赖性杀灭作用，并且在培养中维持的成虫对产卵能力明显受损。