Congeners Derived from Microtubule-Active Phenylpyrimidines Produce a Potent and Long-Lasting Paralysis of Schistosoma mansoni In Vitro

Abstract

Schistosomiasis is a parasitic disease that affects approximately 200 million people in developing countries. Current treatment relies on just one partially effective drug, and new drugs are needed. Tubulin and microtubules (MTs) are essential constituents of the cytoskeleton in all eukaryotic cells and considered potential drug targets to treat parasitic infections. The αand β-tubulin of Schistosoma mansoni have ∼96% and ∼91% sequence identity to their respective human tubulins, suggesting that compounds which bind mammalian tubulin may interfere with MT-mediated functions in the parasite. To explore the potential of different classes of tubulin-binding molecules as antischistosomal leads, we completed a series of in vitro wholeorganism screens of a target-based compound library against S. mansoni adults and somules (postinfective larvae), and identified multiple biologically active compounds, among which phenylpyrimidines were the most promising. Further structure−activity relationship studies of these hits identified a series of thiophen-2-yl-pyrimidine congeners, which induce a potent and long-lasting paralysis of the parasite. Moreover, compared to the originating compounds, which showed cytotoxicity values in the low nanomolar range, these new derivatives were 1−4 orders of magnitude less cytotoxic and exhibited weak or undetectable activity against mammalian MTs in a cell-based assay of MT stabilization. Given their selective antischistosomal activity and relatively simple druglike structures, these molecules hold promise as candidates for the development of new treatments for schistosomiasis.

The discovery of a novel series of compounds with single-dose efficacy against juvenile and adult Schistosoma species

“…This paper documents the discovery of a potent series of anti-schistosomiasis compounds with excellent prospects for achieving a single dose cure in humans that stand out from those reported in a recent extensive review of the field [17] and series reported since that review [29][30][31]. The weakly potent original hits have been optimised to compounds with approximately three orders of magnitude better in vitro potency.…”

Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence

“…The overall motility of worms, measured for each well, is determined by two algorithms: one that calculates the average velocity of moving contours inside the well and another which detects changes in the occupation and vacancy of pixels between a group of frames. WormAssay quantified the effect of several compounds on worm motility, including neuromodulatory drugs (79), phenylpyrimidines (80) and inhibitors of S. mansoni cyclic nucleotide phosphodiesterase 4 (SmPDE4) (81) and proteasome (82). Recently, a modified version of WormAssay software, named WormAssayGP2, was released by Padalino and colleagues (83,84) and contains minor modifications related to the source code and user interface (85).…”

Drug Repurposing and De Novo Drug Discovery of Protein Kinase Inhibitors as New Drugs against Schistosomiasis

“…Accordingly, this area has also been broadly addressed for schistosomiasis, in which several different classes of synthetic compounds have been created, optimized, and studied, such as biaryl alkyl carboxylic acids [42,43], trioxolanes [44][45][46], aryl ozonides [47], tetraazamacrocyclics [48], etc. [49][50][51][52][53][54][55][56]. Although most of these synthetic derivatives show satisfactory antiparasitic properties against Schistosoma in vitro and/or in vivo, there is still a wide knowledge gap regarding ligand-target interactions.…”