Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185, Rome, Italy.
Research Laboratories, Bambino Gesù Children's Hospital-IRCCS, 00146, Rome, Italy.
ChemMedChem. 2023 Feb 1;18(3):e202200510. doi: 10.1002/cmdc.202200510. Epub 2022 Nov 8.
Schistosoma mansoni HDAC8 is a reliable target to fight schistosomiasis, and several inhibitors have been reported in the literature up to now. Nevertheless, only a few displayed selectivity over the human deacetylases and some exhibited very low or no activity against parasite larvae and/or adult worms. We report here the in vitro enzyme and biological activity of a small library of HDAC inhibitors from our lab, in many cases exhibiting submicromolar/nanomolar potency against smHDAC8 and diverse degrees of selectivity over hHDAC1 and/or hHDAC6. Such compounds were tested against schistosomula, and a selection of them against the adult forms of S. mansoni, to detect their effect on viability. Some of them showed the highest viability reduction for the larval stage with IC values around 1 μM and/or displayed ∼40-50 % activity in adult worms at 10 μM, joined to moderate to no toxicity in human fibroblast MRC-5 cells.
曼氏血吸虫 HDAC8 是治疗血吸虫病的可靠靶点，迄今为止，已有文献报道了几种抑制剂。然而，只有少数几种抑制剂对人源去乙酰化酶具有选择性，并且有些抑制剂对寄生虫幼虫和/或成虫的活性非常低或没有。我们在此报告了来自我们实验室的一小部分 HDAC 抑制剂的体外酶和生物学活性，在许多情况下，这些抑制剂对 smHDAC8 的活性具有亚微摩尔/纳摩尔的效力，并且对 hHDAC1 和/或 hHDAC6 具有不同程度的选择性。这些化合物被测试了对毛蚴的活性，并且选择了一些化合物来测试它们对曼氏血吸虫成虫的活性，以检测它们对生存力的影响。其中一些化合物在幼虫阶段的存活率降低方面表现出最高的活性，IC 值约为 1μM，并且在 10μM 时对成虫的活性约为 40-50%，同时对人成纤维细胞 MRC-5 细胞的毒性适中或没有。
