十二指肠贾第鞭毛虫是一种广泛存在的寄生鞭毛原生动物，可引起贾第鞭毛虫病，每年影响数百万人，尤其是儿童和旅行者。由于没有有效的疫苗，治疗主要依靠口服针对小肠滋养体的药物。然而，现有药物由于副作用和耐药性而带来挑战，因此需要探索新的治疗选择。异隐托平 (Isocryptolepine) 源自 Cryptolepis sanguinolenta，已被证明具有良好的抗菌和抗癌特性。这项研究评估了 18 种异隐松三唑加合物的抗贾虫药活性和细胞毒性，其中 ISO2 表现出强大的抗贾虫药活性和对人体肠道细胞的最小细胞毒性。代谢组学分析显示，ISO2 处理后十二指肠球菌代谢发生显着变化，特别是影响磷脂代谢。值得注意的是，植物鞘氨醇和甘油三酯的上调以及某些脂肪酸的下调表明对膜组成和完整性产生深远影响，可能导致寄生虫的死亡。通路分析强调甘油磷脂代谢、细胞色素 b5 家族血红素/类固醇结合域和 P 型 ATP 酶机制是受 ISO2 治疗影响的关键通路，强调其作为抗贾第药治疗潜在靶点的重要性。这些发现揭示了 ISO2 对抗十二指肠球菌的作用方式，并为进一步的药物开发提供了宝贵的见解。此外，该研究还为探索异隐脑碱衍生物作为贾第鞭毛虫病的新型治疗剂提供了一条有前途的途径，解决了对更有效、更安全的治疗方案的迫切需求。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

Giardia duodenalis, a widespread parasitic flagellate protozoan causing giardiasis, affects millions annually, particularly impacting children and travellers. With no effective vaccine available, treatment primarily relies on the oral administration of drugs targeting trophozoites in the small intestine. However, existing medications pose challenges due to side effects and drug resistance, necessitating the exploration of novel therapeutic options. Isocryptolepine, derived from Cryptolepis sanguinolenta, has demonstrated promising antimicrobial and anticancer properties. This study evaluated eighteen isocryptolepine-triazole adducts for their antigiardial activities and cytotoxicity, with ISO2 demonstrating potent antigiardial activity and minimal cytotoxicity on human intestinal cells. Metabolomics analysis revealed significant alterations in G. duodenalis metabolism upon ISO2 treatment, particularly affecting phospholipid metabolism. Notably, the upregulation of phytosphingosine and triglycerides, and downregulation of certain fatty acids, suggest a profound impact on membrane composition and integrity, potentially contributing to the parasite's demise. Pathway analysis highlighted glycerophospholipid metabolism, cytochrome b5 family heme/steroid binding domain, and P-type ATPase mechanisms as critical pathways affected by ISO2 treatment, underscoring its importance as a potential target for antigiardial therapy. These findings shed light on the mode of action of ISO2 against G. duodenalis and provide valuable insights for further drug development. Moreover, the study also offers a promising avenue for the exploration of isocryptolepine derivatives as novel therapeutic agents for giardiasis, addressing the urgent need for more effective and safer treatment options.Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.