Novel congeners derived from microtubule-active phenylpyrimidines produce a potent and long-lasting paralysis of Schistosoma mansoni in vitro

• Published in: ACS infectious diseases 2020-10, Vol.7 (5), p.1089-1103
• Main Authors: Monti, Ludovica, Cornec, Anne-Sophie, Oukoloff, Killian, Kovalevich, Jane, Prijs, Kristen, Alle, Thibault, Brunden, Kurt R., Smith, Amos B., El-Sakkary, Nelly, Liu, Lawrence J., Syed, Ali, Skinner, Danielle E., Ballatore, Carlo, Caffrey, Conor R.
• Format: Article
• Language: English
• ISSN: 2373-8227
• DOI: 10.1021/acsinfecdis.0c00508

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 α- and 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 anti-schistosomal leads, we completed a series of in vitro whole-organism screens of a target-based compound library against S. mansoni adults and somules (post-infective 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 novel 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 anti-schistosomal activity and relatively simple drug-like structures, these molecules hold promise as candidates for the development of new treatments for schistosomiasis.