有机二硫类血吸虫SjTrx抑制剂的合成及抗虫活性筛选研究

Schistosomiasis is a devastating zoonotic parasitic disease that harms human health and affects social development. Currently, the treatment of schistosomiasis solely depends on a specific agent, i.e., praziquantel, which also increases the risk of drug resistance. Therefore, there is an urgent requirement of developing alternative antischistosomal drugs for schistosomiasis treatment. With thioredoxin protein of Schistosoma japonicum (SjTrx) as the target, this project focuses on the design and synthesis of novel organic disulfide compounds. The reversible or irreversible redox reaction of these exogenous organic disulfide compounds with the sulfhydryl groups of WCGPC in SjTrx can undermine the critical redox balance of Schistosoma japonicum, further leading to Schistosoma death and achieving the purpose of Schistosomiasis control. The major research contents are as follows: (1) design and synthesis of novel disulfide compounds SjTrx inhibitors using SjTrx as the target by molecular docking; (2) insecticidal activity study of disulfide compounds against S. japonicum cercariae, schistosomula and adult schistosome; (3)Toxicities of synthesized compounds; (4)SjTrx and the other key enzymes inhibitory activities and mechanism study of disulfide compounds. These results will help in screening strong insecticidal SjTrx inhibitors, as well as laying a solid foundation for the subsequent development of antischistosomal drugs.

血吸虫病是一种严重危害人类健康，影响社会发展的人畜共患寄生虫病。吡喹酮作为治疗日本血吸虫病的唯一特效药，其耐药性问题引起了广泛关注，研制新的替代药物刻不容缓。本项目以日本血吸虫硫氧还蛋白（SjTrx）为靶标，设计合成一系列新型有机二硫化合物，这种外源性有机二硫化合物与日本血吸虫硫氧还蛋白结合后，进而与蛋白活性位点WCGPC中的巯基发生可逆或不可逆氧化还原反应，破坏血吸虫体内氧化还原平衡这一关键生命过程导致血吸虫死亡、达到治疗血吸虫病的目的。研究内容：（1）以日本血吸虫SjTrx为药物作用靶点，通过分子对接，设计合成有机二硫化合物SjTrx抑制剂；（2）研究药物抗血吸虫尾蚴、童虫和成虫活性；（3）研究药物毒性；（4）研究药物对SjTrx及关键酶活性的影响，探索药物作用机理。通过本项目的实施，期望筛选出抗虫活性强的SjTrx抑制剂，为后续抗血吸虫药物的研制奠定基础。

血吸虫严重危害人类健康和社会发展。针对血吸虫成虫，我们设计和合成了一系列有机二硫化合物，硫代磺酸酯类化合物以及其他含硫有机化合物，鉴定了这些化合物的结构，优化了合成条件。在此基础上，研究了这些化合物抗血吸虫活性。对筛选出的较好的化合物，研究了这类化合物的初步机理和毒性。分析和总结了结构和活性之间的关系。特别是筛选出了一种抗虫效果较好的吗啉取代的噻唑烷酮类化合物。撰写和发表了学术论文10篇。申请了相关国家发明专利2项，授权1项。