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

Abstract Three sub-series of 3-benzylmenadiones were discovered as new antischistosomal agents. The most potent representatives, called schistodiones, exhibited IC50 values <5 μM against larvae and ex vivoSchistosoma mansoni adult worms and moderate activity per os in the S. mansoni-infected mouse model in vivo. 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 S. mansoni 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 a synthase inhibition. These two drug targets are discussed in the context of S.mansoni biology, with S. mansoni thioredoxin–glutathione reductase redox-cycling and a potential source of oxidative stress in the parasite.