Design, synthesis and preliminary structure-activity relationship of 2-iminothiazolidine-4-one derivatives against Schistosoma japonicum in vitro and in vivo

Abstract

Schistosomiasis, ranking second only to malaria in prevalence, is considered as a significant infectious parasitic disease in tropical and subtropical regions. Current therapeutic and control paradigms remain predominantly dependent on praziquantel monotherapy, highlighting the urgent need for alternative chemotherapeutic agents. Herein, we demonstrate the discovery and preliminary structure-activity relationship of 2-iminothiazolidine-4-one derivatives targeting Schistosoma japonicum in vitro and in vivo. The screening identified several hit compounds in this series exhibiting micromolar-level activity against the adult stage of the parasite in vitro, with a distinct mechanism involving tegumental disintegration of the worms. Notably, compound 17 exhibited potent in vitro activity against adult S. japonicum, with an LC₅₀ (72 h) value of 25.31 ± 1.40 μM. In murine models of schistosomiasis, intraperitoneal administration of compound 17 (25 mg/kg/day × 7) achieved significant worm burden reduction of 52 % and 26 % in adult and juvenile stages, respectively. Furthermore, in vivo therapeutic assessments revealed that the hit compounds not only alleviated liver lesions but also demonstrated safety profiles with low hepatotoxicity. Acute oral toxicity experiments showed that compound 17 also possesses low oral toxicity and maintains an acceptable hepatotoxicological profile. These findings establish the ethyl 4-oxo-2-iminothiazolidin-5-ylidene acetate pharmacophore as a privileged scaffold for schistosomicidal development, providing a robust foundation for subsequent lead optimization toward next-generation antischistosomal therapeutics.