Schistosomiasis is an important prevalent disease in approximately 80 countries in tropical and subtropical regions, ranking second only to malaria in prevalence [1]. As a neglected tropical disease, schistosomiasis causes approximately 200,000 annual fatalities, infecting over 200 million individuals globally [2]. Three main schistosome species including Schistosoma haematobium, Schistosoma mansoni and Schistosoma japonicum are known to infect human beings [3]. In China, schistosomiasis is caused by Schistosoma japonicum with an intermediate host (Oncomelania snails), which remains a significant public health challenges despite control efforts [4].

Although veterinary vaccines have been developed for buffaloes and pigs, challenges including quality-control standardization, batch-to-batch reproducibility, and safety concerns have restricted their application in humans and veterinary medicine [5]. Contemporary control strategies primarily depend on chemotherapeutic interventions [6]. Since its introduction in the 1980s, praziquantel (PZQ) has remained the exclusive therapeutic agent. [7]. However, emerging concerns regarding potential drug resistance and treatment failures necessitate careful consideration, particularly under conditions of mass drug administration and sustained pharmacological pressure [8]. Furthermore, PZQ demonstrates stage-specific efficacy against mature parasites while exhibiting limited activity against juvenile schistosomula [9]. It is necessary to encourage the research and development of new antischistosomal drugs [10].

N/S-containing heterocycles are known for their wide physiological and pharmacological activities in pharmaceutical applications [11]. Among these, thiazolidones and their derivatives exhibit anti-cancer [12], anti-trypanosoma cruzi [13], anti-microbial [14], anti-convulsant [15], antiproliferative [16] and anti-titrypanosomal properties [17]. Recently, thiazolidones have been used as antischistosomal agents against adult worms S. mansoni in vitro. For example, compound (I) demonstrated a moderate worm mortality (<50 %) at 100 μg/mL after 144 h (Fig. 1) [18]. Compound (II) caused 54 % worm mortality at 100 μg/mL after 192 h and compound (III) exhibited complete efficacy (100 % worm mortality) at 100 μM after 72 h [19,20]. These findings suggest that the thiazolidone core scaffold plays important roles as the privileged structural motif for antischistosomal activity. However, existing derivatives display limited antischistosomal activity and have only been evaluated in vitro. In order to address these limitations, this study describes the rational design and systematic synthesis of 42 novel 2-iminothiazolidine-4-one derivatives according to directed pharmacophore-based optimization strategy. Furthermore, antischistosomal potentials against Schistosoma japonicum in vitro and in vivo were explored. Comprehensive evaluation encompassed (i) schistosome survival, (ii) egg output (oviposition inhibition), (iii) motor activity, (iv) tegumental ultrastructural alterations via scanning electron microscopy (SEM), and (v) hepatotoxicity and acute oral toxicity of the selected compounds in murine models, respectively.