ABSTRACT Schistosomiasis is a disease of poverty that infects over 200 million people worldwide and places another 700 million at risk. Current treatment and control of the disease rely on just one drug, praziquantel (PZQ) - a precarious situation should drug resistance emerge. Furthermore, the therapeutic profile of PZQ is not ideal. The World Health Organization has therefore declared schistosomiasis a disease for which new therapies are urgently needed. Microtubules (MTs) are essential components of the cytoskeleton in all eukaryotic cells. MT-targeting drugs, which include MT-stabilizing and -destabilizing compounds, form a cornerstone of cancer chemotherapy; in addition, studies suggest that such compounds may be useful to treat parasitic infections, including schistosomiasis. Accordingly, we phenotypically screened a library of >300 MT-stabilizing agents with generally favorable drug-like properties for anti-schistosomal activity. We identified different members of the phenylpyrimidine (PP) class that exhibited marked bioactivity. Further exploration of the structure activity relationships (SARs) of the most promising compounds identified a series of novel thiophen-2-yl- phenylpyrimidine (TPP) derivatives that produce a potent and long-lasting paralysis of Schistosoma mansoni at compound concentrations that do not elicit MT changes or cytotoxicity in mammalian cells. In light of these in vitro results, these TPPs hold promise as candidate anti-schistosomal agents. The next critical step in the evaluation and development of these compounds as candidate treatments for schistosomiasis is to demonstrate the tolerability and in vivo efficacy of one or more TPP candidates. Towards this end, we propose two aims: (1) Complete structure activity/property relationship studies (SAR/SPR) of 30-50 TPPs through their design, synthesis and in vitro phenotypic evaluation vs. S. mansoni. This will be followed up with pharmacokinetic (PK) analysis of the most promising compounds (3–6) that meet all pre-defined selection criteria for in vitro anti- schistosomal activity, selectivity and “drug-like” physicochemical properties. (2) After the resynthesis of the top 1-3 performing compounds, define their maximum tolerated doses in vivo and subsequently determine their efficacy in a mouse model of S. mansoni infection. The proposed project will provide evidence of a correlation between in vitro and in vivo anti-schistosomal activity, and identify one or more lead structures for future studies that will focus specifically on lead optimization and an understanding of the mechanism of action.