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

## TL;DR

New compounds that inhibit a key enzyme in Schistosoma mansoni worms cause harmful effects in both juvenile and adult stages, suggesting potential as new treatments for schistosomiasis.

## Contribution

Benzodeazaoxaflavin compounds were identified as effective SmSirt2 inhibitors with antiparasitic activity against Schistosoma mansoni.

## Key findings

- Three BDF4-based compounds reduced viability and egg production in Schistosoma mansoni worms.
- The compounds caused histone H3 hyperacetylation and cytochrome c-mediated apoptosis in worms.
- The compounds showed low cytotoxicity in mammalian cells, indicating potential safety for use.

## Abstract

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.