Indole-thiazole derivatives as schistosomicidal agents against Schistosoma mansoni: synthesis, in vitro and in vivo efficacy, immunomodulation, and in silico interaction with cathepsin B1.

Schistosomiasis remains a major neglected tropical disease, and treatment relies almost exclusively on praziquantel, highlighting the need for new schistosomicidal agents. This study evaluated the in vitro and in vivo activity, cytotoxicity, immunomodulatory effects, and potential molecular target of indole-thiazole derivatives against Schistosoma mansoni. Adult worms were assessed for motility, viability, and tegumental alterations, while infected mice were treated to determine parasitological and histopathological outcomes. Cytotoxicity was evaluated in J774-A1 and HepG2 cells, and docking and 100-ns molecular dynamics simulations were performed against S. mansoni cathepsin B1 (SmCB1). JF4 was the most active derivative, with an IC₅₀ of 50.74 μM, causing 100% worm mortality at 100 μM after 24 h. Its selectivity indices were 4.65 and 5.16 for J774-A1 and HepG2 cells, respectively. Scanning electron microscopy revealed tegumental erosions, blebs, and surface disorganization. In vivo, JF4 at 50 mg·kg-1 reduced total worm burden by 65.96% and the mean number of hepatic granulomas by 59.8%. Oogram analysis showed 29.2 ± 4.38% immature eggs, 21.6 ± 5.89% mature eggs, and 49.2 ± 2.28% dead eggs. JF4 also modulated splenocyte inflammatory responses without compromising regulatory markers or inducing oxidative stress. Molecular dynamics showed stabilization after approximately 50 ns, with Cα RMSD near 1.5 Å, ligand RMSD near 1 Å, and radius of gyration around 18 Å. These findings identify JF4 as the most promising derivative and support SmCB1 as a plausible molecular target.