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Inhibitors of Schistosoma mansoni Redox Cascade

Schistosomiasis is one of the most important human parasitic diseases in terms of morbidity and mortality. Only one drug is currently available for treatment of schistosomiasis; new drugs are urgently needed. Studies on schistosome redox balance mechanisms indicate a distinct and compressed pathway in the parasite compared to its human host. The probe compound described below (SID 11111612) was discovered after a high throughput screening, informatics, and medicinal chemistry campaign. This probe is a nitric oxide donor that exhibits anti-schistosomal activity against worms in ex vivo assays. It is a potential lead for therapeutic development for the treatment of schistosomiasis, a neglected disease in the developing world.

Structure of Fuxoran

SID 11111612
NCGC00015800
Furoxan

Key Investigators

National Center for Advancing Translational Sciences
Ajit Jadhav
Wendy Lea, Ph.D.
David Maloney, Ph.D.
Ganesha Rai, Ph.D.
Anton Simeonov, Ph.D.
Craig Thomas, Ph.D.

Rush University Medical Center
David L. Williams, Ph.D.

Public Health Impact

Schistosomiasis is a debilitating disease affecting approximately 250 million people in more than 70 countries. Current drug treatments are limited, and the parasites causing the disease are becoming resistant to these drugs. This probe compound exhibits anti-schistosomal activity, and serves as a potential lead for anti-schistosomal drug development.

Publications

Lea WA, Jadhav A, Rai G, et al. A 1,536-well-based kinetic HTS assay for inhibitors of Schistosoma mansoni thioredoxin glutathione reductase. Assay Drug Dev Technol, 2008;6:551-555.

Simeonov A, Jadhav A, Sayed AA, et al. Quantitative high-throughput screen identifies inhibitors of the Schistosoma mansoni redox cascade. PLoS Negl Trop Dis, 2008;2:1-10; e127.

Sayed AA, Simeonov A, Thomas CJ, et al. Identification of oxadiazoles as new drug leads for the control of schistosomiasis. Nat Med, 2008;14:407-412.

Rai G, Sayed AA, Lea WA, et al. Structure mechanism insights and the role of nitric oxide donation guide the development of oxadiazole-2-oxides as therapeutic agents against schistosomiasis. J Med Chem, 2009;52:6474-6483.

Rai G, Thomas CJ, Leister W, Maloney DJ. Synthesis of oxadiazole-2-oxide analogues as potential antischistosomal agents. Tett Lett, 2009;50:1710-1713.

Probe Report

Inhibitors of Schistosoma Mansoni Redox Cascade