Department of Immunology, Laboratory of Immunopathology and Molecular Biology, Aggeu Magalhães Institute, FIOCRUZ, Recife, PE, Brazil.
Department of Pharmaceutical Sciences, Federal University of Pernambuco (UFPE), S/N, Recife, PE, CEP 50740-525, Brazil.
Parasitol Res. 2022 Jul;121(7):2111-2120. doi: 10.1007/s00436-022-07533-4. Epub 2022 May 23.
Schistosomiasis mansoni is considered a serious public health problem. As praziquantel is the only drug recommended by the World Health Organization for the treatment and control of schistosomiasis, the development of new drugs is of great significance. In this work, we present the antischistosomal activity of a small set of phthalimido-thiazole derivatives against Schistosoma mansoni. The effects of those derivatives on the viability of larvae juveniles and adult parasites, production and development of eggs, mortality of schistosomules in vitro by counting worms, and stages of eggs of infected animals in acute and chronic phases were evaluated, resulting in the identification of new multistage antischistosomal compounds. Additionally, a study of liver fibrogenesis was released. The phthalimido-thiazole derivatives, compounds 2b-d, 2h-j, had shown activity on schistosomules, achieving 100% mortality even at 5 mg/mL, in the first 24 h. In the chronic phase of schistosomiasis infection, compound 2i promoted a reduction in the number of immature eggs, an increase in the number of non-viable parasite eggs, a reduction in the average number of eggs in the liver and intestine, decrease in the levels of hydroxyproline in the liver, and a reduction in the areas of hepatic fibrosis. This compound also promoted an increase of IL-10 and a reduction in the level of TNF-α in the liver. Accordingly, the phthalimide-thiazole scaffold is a new starting point for the development of multistage compounds that affect S. mansoni viability, egg formation, and production.
曼氏血吸虫病被认为是一个严重的公共卫生问题。由于吡喹酮是世界卫生组织推荐用于治疗和控制血吸虫病的唯一药物，因此开发新药物具有重要意义。在这项工作中，我们研究了一小部分邻苯二甲酰亚胺噻唑衍生物对曼氏血吸虫的抗血吸虫活性。评估了这些衍生物对幼虫、成虫活力、卵的产生和发育、体外感染动物急性和慢性阶段的尾蚴死亡率以及卵的各个阶段的影响，从而鉴定了新的多阶段抗血吸虫化合物。此外，还进行了肝纤维化的研究。邻苯二甲酰亚胺噻唑衍生物 2b-d、2h-j 对尾蚴具有活性，在第 24 小时内，即使在 5 mg/mL 时，也能达到 100%的死亡率。在血吸虫病感染的慢性阶段，化合物 2i 促进了不成熟卵数量的减少、寄生虫卵活力的增加、肝和肠内卵数量的减少、肝羟脯氨酸水平的降低以及肝纤维化面积的减少。该化合物还促进了肝组织中 IL-10 的增加和 TNF-α 水平的降低。因此，邻苯二甲酰亚胺噻唑支架是开发影响曼氏血吸虫活力、卵形成和产生的多阶段化合物的新起点。
