Synthesis and Antischistosomal Activity Profile of Several Sub-Series of Redox-Active Lead 3‑BenzylmenadionesInvestigations of the Modes of Action in Yeast

The most potent representatives, called schistodiones, exhibited IC₅₀ values <5 μM against larvae and <i>ex vivo</i> Schistosoma mansoni adult worms and moderate activity <i>per os</i> in the <i>S. mansoni</i>-infected mouse model <i>in vivo</i>. We synthesized the putative 3-benzoylmenadione metabolites of the most active compounds and explored the possible mode(s) of action using the yeast model and the recombinant drug target <i>S. mansoni</i> thioredoxin-glutathione reductase.

Two drug targets were identified in yeast: the yeast NADH dehydrogenase and Cox15, involved in events responsible for respiratory growth defect in yeast, respectively: (i) the bioreductive activation step producing reactive oxygen species and (ii) the heme <i>a</i> synthase inhibition. These two drug targets are discussed in the context of <i>S.mansoni</i> biology, with <i>S. mansoni</i> thioredoxin–glutathione reductase redox-cycling and a potential source of oxidative stress in the parasite.