Schistosomiasis is a neglected disease of poverty that is caused by infection with blood fluke species contained within the genus Schistosoma . For the last 40 years, control of schistosomiasis in endemic regions has predominantly been facilitated by administration of a single drug, praziquantel. Due to limitations in this mono-chemotherapeutic approach for sustaining schistosomiasis control into the future, alternative anti-schistosomal compounds are increasingly being sought by the drug discovery community. Herein, we describe a multi-pronged, integrated strategy that led to the identification and further exploration of the quinoxaline core as a promising anti-schistosomal scaffold. Firstly, phenotypic screening of commercially available small molecules resulted in the identification of a moderately active hit compound against Schistosoma mansoni (1, EC 50 = 4.59 μM on schistosomula). Secondary exploration of the chemical space around compound 1 led to the identification of a quinoxaline-core containing, non-genotoxic lead (compound 22). Compound 22 demonstrated substantially improved activities on both intra-mammalian (EC 50 = 0.44 μM, 0.20 μM and 84.7 nM, on schistosomula, juvenile and adult worms, respectively) and intra-molluscan (sporocyst) S. mansoni lifecycle stages. Further medicinal chemistry optimisation of compound 22, resulting in the generation of 20 additional analogues, improved our understanding of the structure-activity relationship and resulted in considerable improvements in both anti-schistosome potency and selectivity (e.g. compound 30; EC 50 = 2.59 nM on adult worms; selectivity index compared to the HepG2 cell line = 348). Some derivatives of compound 22 (e.g. 31 and 33) also demonstrated significant activity against the two other medically important species, Schistosoma haematobium and Schistosoma japonicum . Further optimisation of this class of anti-schistosomal is ongoing and could lead to the development of an urgently needed alternative to praziquantel for assisting in schistosomiasis elimination strategies.

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We construct a database of federal appellate cases involving religious liberties decided between 2006 and 2015, expanding and improving an existing database covering up to 2005. The data are used to investigate the role of religion in judicial decision making. We find that Jewish judges are significantly more likely than their non‐Jewish colleagues to favor claimants in religious liberties cases, but we find no significant effects for other minority religions. Our findings confirm previous findings in the literature, but we go a number of steps further than existing studies in uncovering the sources of Jewish judges’ influence. We conclude that the effect of Jewish judges comes through their increased concern for the separation of church and state—not through their heightened solicitude for the interests of religious minorities in practicing their religion or through preferential treatment of Jewish claimants. Further, our analysis of cases not involving religion shows that the pro‐claimant effect of Jewish judges is attributable not to a general liberal attitude but to a particular secular concern for the separation of church and state. Finally, we are the first researchers to go beyond individual effects and investigate the panel effects of judges’ religious affiliation. Our findings in this regard have suggestive implications for identifying the mechanism of panel effects.

Schistosomiasis is a chronic and painful disease of poverty caused by the flatworm parasite Schistosoma . Drug discovery for antischistosomal compounds predominantly employs in vitro whole organism (phenotypic) screens against two developmental stages of Schistosoma mansoni , post-infective larvae (somules) and adults. We generated two rule books and associated scoring systems to normalize 3898 phenotypic data points to enable machine learning. The data were used to generate eight Bayesian machine learning models with the Assay Central software according to parasite’s developmental stage and experimental time point (≤24, 48, 72, and >72 h). The models helped predict 56 active and nonactive compounds from commercial compound libraries for testing. When these were screened against S. mansoni in vitro , the prediction accuracy for active and inactives was 61% and 56% for somules and adults, respectively; also, hit rates were 48% and 34%, respectively, far exceeding the typical 1–2% hit rate for traditional high throughput screens.

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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.

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Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT‐active compounds hold promise as antitrypanosomal agents. MT‐targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,β‐tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against cultured Trypanosoma brucei enabled a robust quantitative structure‐activity relationship (QSAR) model and the prioritization of two congeners for in vivo pharmacokinetics (PK), tolerability and efficacy studies. Treatment of T. brucei‐infected mice with tolerable doses of TPDs significantly decreased blood parasitemia within 24 h. Further, two once‐weekly doses at 10 mg/kg of a candidate TPD significantly extended the survival of infected mice relative to infected animals treated with vehicle. Further optimization of dosing and/or the dosing schedule of these CNS‐active TPDs may provide alternative treatments for human African trypanosomiasis.