Benzodeazaoxaflavin Sirtuin Inhibitors Inhibit Schistosoma mansoni Sirt2 and Cause Phenotypic Changes and Lethality in Schistosomula and Adult Worm Stages

Schistosomiasis, a neglected tropical disease caused by trematodes of Schistosoma genus, urgently requires new treatments due to praziquantel's limited efficacy against juvenile worms as well as the threat of drug resistance. In this study, we evaluated a series of benzodeazaoxaflavin (BDF4)-based compounds as inhibitors of the parasite's epigenetic enzyme SmSirt2. Three compounds, 7-9 (MC2346, MC2141, and MC2345), showed activity against both Liberian and Puerto Rican strains of Schistosoma mansoni. The compounds reduced schistosomula and adult worm pair viability, pairing, and egg production, with low cytotoxicity in mammalian cells. These effects were linked to histone H3 hyperacetylation and cytochrome c-mediated apoptosis, confirming SmSirt2 as a functional target. These findings support the development of SmSirt2 inhibitors as novel antischistosomal agents with therapeutic potential for both curative and preventive applications. Further in vivo studies are warranted to assess their pharmacokinetic and safety profiles.