Discovery of New Anti-Schistosomal Hits by Integration of QSAR-Based Virtual Screening and High Content Screening

Schistosomiasis
is a debilitating neglected tropical disease, caused
by flatworms of Schistosoma genus.
The treatment relies on a single drug, praziquantel (PZQ), making
the discovery of new compounds extremely urgent. In this work, we
integrated QSAR-based virtual screening (VS) of Schistosoma
mansoni thioredoxin glutathione reductase (SmTGR) inhibitors and high content screening (HCS) aiming
to discover new antischistosomal agents. Initially, binary QSAR models
for inhibition of SmTGR were developed and validated
using the Organization for Economic Co-operation and Development (OECD)
guidance. Using these models, we prioritized 29 compounds for further
testing in two HCS platforms based on image analysis of assay plates.
Among them, 2-[2-(3-methyl-4-nitro-5-isoxazolyl)­vinyl]­pyridine and
2-(benzylsulfonyl)-1,3-benzothiazole, two compounds representing new
chemical scaffolds have activity against schistosomula and adult worms
at low micromolar concentrations and therefore represent promising
antischistosomal hits for further hit-to-lead optimization.