Department of Pharmaceutical Chemistry, Philipps-Universität Marburg, Marbacher, Weg 6, 35032, Marburg, Germany.
BFS, Institute of Parasitology, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392, Gießen, Germany.
Eur J Med Chem. 2022 Nov 15;242:114641. doi: 10.1016/j.ejmech.2022.114641. Epub 2022 Aug 18.
Schistosomiasis is a neglected tropical disease with more than 200 million new infections per year. It is caused by parasites of the genus Schistosoma and can lead to death if left untreated. Currently, only two drugs are available to combat schistosomiasis: praziquantel and, to a limited extent, oxamniquine. However, the intensive use of these two drugs leads to an increased probability of the emergence of resistance. Thus, the search for new active substances and their targeted development are mandatory. In this study the substance class of "dithiocarbamates" and their potential as antischistosomal agents is highlighted. These compounds are derived from the basic structure of the human aldehyde dehydrogenase inhibitor disulfiram (tetraethylthiuram disulfide, DSF) and its metabolites. Our compounds revealed promising activity (in vitro) against adults of Schistosoma mansoni, such as the reduction of egg production, pairing stability, vitality, and motility. Moreover, tegument damage as well as gut dilatations or even the death of the parasite were observed. We performed detailed structure-activity relationship studies on both sides of the dithiocarbamate core leading to a library of approximately 300 derivatives (116 derivatives shown here). Starting with 100 μm we improved antischistosomal activity down to 25 μm by substitution of the single bonded sulfur atom for example with different benzyl moieties and integration of the two residues on the nitrogen atom into a cyclic structure like piperazine. Its derivatization at the 4-nitrogen with a sulfonyl group or an acyl group led to the most active derivatives of this study which were active at 10 μm. In light of this SAR study, we identified 17 derivatives that significantly reduced motility and induced several other phenotypes at 25 μm, and importantly five of them have antischistosomal activity also at 10 μm. These derivatives were found to be non-cytotoxic in two human cell lines at 100 μm. Therefore, dithiocarbamates seem to be interesting new candidates for further antischistosomal drug development.
血吸虫病是一种被忽视的热带病，每年有超过 2 亿例新感染病例。它是由血吸虫属寄生虫引起的，如果不治疗，可能导致死亡。目前，只有两种药物可用于治疗血吸虫病：吡喹酮和在一定程度上的奥沙米酮。然而，这两种药物的大量使用会增加产生耐药性的可能性。因此，寻找新的活性物质并对其进行靶向开发是强制性的。在这项研究中，强调了“二硫代氨基甲酸盐”类物质及其作为抗血吸虫药物的潜力。这些化合物是从人类醛脱氢酶抑制剂双硫仑（四乙基硫代秋兰姆二硫化物，DSF）及其代谢物的基本结构衍生而来的。我们的化合物对曼氏血吸虫成虫表现出有希望的活性（体外），例如减少产卵、配对稳定性、活力和运动性。此外，还观察到表皮损伤以及肠道扩张甚至寄生虫死亡。我们对二硫代氨基甲酸盐核心的两侧进行了详细的构效关系研究，得到了大约 300 个衍生物的库（这里显示了 116 个衍生物）。从 100 μm 开始，我们通过用不同的苄基取代单键硫原子，将抗血吸虫活性提高到 25 μm，并将两个氮原子上的残基整合到类似哌嗪的环状结构中，从而提高了抗血吸虫活性。在 4-氮上用磺酰基或酰基进行衍生化，得到了本研究中最活跃的衍生物，其在 10 μm 时就具有活性。根据这项 SAR 研究，我们确定了 17 种衍生物，它们在 25 μm 时显著降低了运动性并诱导了其他几种表型，其中重要的是，有 5 种衍生物在 10 μm 时也具有抗血吸虫活性。这些衍生物在两种人类细胞系中在 100 μm 时没有细胞毒性。因此，二硫代氨基甲酸盐似乎是进一步抗血吸虫药物开发的有前途的新候选药物。
