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Identification of oxadiazoles as new drug leads for the control of schistosomiasis

Abstract

Treatment for schistosomiasis, which is responsible for more than 280,000 deaths annually, depends almost exclusively on praziquantel. Millions of people are treated annually with praziquantel, and drug-resistant parasites thus are likely to evolve. Phosphinic amides and oxadiazole 2-oxides, identified from a quantitative high-throughput screen, were shown to inhibit a parasite enzyme, thioredoxin glutathione reductase (TGR), with activities in the low micromolar to low nanomolar range. Incubation of parasites with these compounds led to rapid inhibition of TGR activity and parasite death. The activity of the oxadiazole 2-oxides was associated with a donation of nitric oxide. Treatment of schistosome-infected mice with 4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide led to marked reductions in worm burdens from treatments against multiple parasite stages and egg-associated pathologies. The compound was active against the three major schistosome species infecting humans. These protective effects exceed benchmark activity criteria set by the World Health Organization for lead compound development for schistosomiasis.

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Figure 1: Activity of oxadiazole 2-oxides and phosphinic amides against thioredoxin glutathione reductase and cultured Schistosoma mansoni worms.
Figure 2: The action of compounds 3 and 9 on thioredoxin glutathione reductase activities in extracts prepared from cultured Schistosoma mansoni worms.
Figure 3: In vivo drug treatment with compound 9.

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Acknowledgements

This work was supported in part by US National Institutes of Health (NIH)/National Institute of Mental Health grant R03MH076449 (D.L.W.) and by NIH/National Institute of Allergy and Infectious Diseases (NIAID) grant R01AI065622 (D.L.W.), and in part by the NIH Roadmap for Medical Research Molecular Libraries Program. Schistosome life stages used in this research were supplied in part by the NIAID Schistosomiasis Resource Center at the Biomedical Research Institute (Rockville, Maryland, USA) through NIAID Contract N01-AI-30026.

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Contributions

A.A.S., A.S. and D.L.W. designed the research. A.A.S. performed enzyme, cultured worm and in vivo experiments. A.A.S. and D.L.W. analyzed the data. C.J.T. and A.S. contributed oxadiazole 2-oxide reagents. A.A.S., D.L.W., A.S., J.I., C.J.T. and C.P.A. discussed the results and wrote the paper.

Corresponding authors

Correspondence to Christopher P Austin or David L Williams.

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Sayed, A., Simeonov, A., Thomas, C. et al. Identification of oxadiazoles as new drug leads for the control of schistosomiasis. Nat Med 14, 407–412 (2008). https://doi.org/10.1038/nm1737

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