Molecular containment of iron source inhibits larval survival of Schistosoma mansoni and egg-laying behavior of the female adult worms via ovarian atrophy.

Background: Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma. Currently, praziquantel is the only medication available for treating schistosomiasis. However, crucial issues regarding drug resistance, reinfection, and prevention remain unresolved. Therefore, it is indispensable to develop new antischistosomal drugs, whose mechanisms of action are distinct from that of praziquantel. This diversification in treatment is vital to promote the eradication of schistosomiasis.

Methods: In this study, to explore the untapped antischistosomal compounds against Schistosoma species, which have diverse life cycles, we initially investigated the effects of a series of phenanthroline-based compounds (PHN-X) with iron-binding affinity on the survival capacity of Schistosoma mansoni larvae and egg production by paired adult worms in vitro. Subsequently, we examined the impacts of PHN-X on the egg production and fecundity of female adult worms in vivo, following oral administration of them to mice infected with S. mansoni cercariae. Finally, we conducted a morphological analysis of the reproductive organs of the female adult worms after treating S. mansoni-infected mice with a newly identified compound with high anti-fecundity effect.

Results: The assay for determining IC₅₀ and IC₉₀ values against schistosomula indicated that PHN-X effectively led to larval death, unlike deferoxamine and praziquantel. The larvicidal activity depended on the strength of the coordination bonds between its nitrogen atoms and an iron ion. Furthermore, PHN-X with electron-donating groups substantially inhibited the egg-laying behavior of paired adult worms in vitro. Notably, orally administrating PHN-(OMe)₂ with two methoxy groups to S. mansoni-infected mice decreased the egg production rate of the female adult worms. The analyses of the ovarian area and the reaction of PHN-(OMe)₂ with iron ions indicated that containment of Fe(II) ions caused abnormal ovarian atrophy, contributing to the expression of its anti-fecundity effect in vivo.

Conclusions: PHN-(OMe)₂, which has an affinity for Fe(II) ion-binding affinity, significantly affected the survival of larvae and egg-laying behavior of female adult worms. Thus, the strategy for containing the iron source required by S. mansoni could offer valuable insight for developing new drugs to diversify the treatment options for schistosomiasis.