Schistosomiasis is a neglected tropical disease caused by parasitic bloodflukes of the genus Schistosoma. Although hundreds of millions of individuals are infected or at risk of infection, current therapy relies precariously on just one drug, praziquantel. Our recent studies suggest that microtubules (MTs) are a promising target for treatment of schistosomiasis. Evaluation of MT-active compounds using in vitro whole-organism screens show that non-naturally occurring MT-active compounds are effective against S. mansoni. Through the design, synthesis and evaluation of a series of phenylpyrimidines (Figure 1, PPDs), the thiophenyl PPD emerged as a promising series due to its unique and long-lasting paralysis of S. mansoni combined with limited toxicity in mammalian cells [Monti, L. et. al., ACS Infect. Dis. 2020, 7, 1089−1103]. To further elucidate the structure-activity and structure-property relationships (SAR/SPR) and identify improved candidates, a library comprising >50 thiophenyl PPD congeners were designed, synthesized and evaluated against S. mansoni. The SAR data, which highlighted some important differences with the previously established anticancer SAR of PPDs, resulted in selective, potent anti-schistosomal agents that exhibit potentially favorable drug-like properties.

<b>Figure 1:</b> SAR and SPR of PPDs have led to analogs with potent paralytic effect on <i>S. mansoni</i>, limited cytotoxicity in mammalian cells, and improved physicochemical properties.

Figure 1: SAR and SPR of PPDs have led to analogs with potent paralytic effect on S. mansoni, limited cytotoxicity in mammalian cells, and improved physicochemical properties.

Thibault Alle

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