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United States Department of Agriculture

Agricultural Research Service

Research Project: Integrated Approach to the Detection and Control of Foodborne Parasites and the Impact on Food Safety

Location: Animal Parasitic Diseases

Title: Salicylanilide inhibitors of Toxoplasma gondii

item Fomovska, Alina
item Wood, Richard
item Mui, Ernst
item Welsh, William
item Dubey, Jitender
item Ferreira, Leandra
item Hickman, Mark
item Lee, Patricia
item Leed, Susan
item Auschwitz, Jennifer
item Sommerville, Caroline
item Woods, Stuart
item Roberts, Craig
item Mcleod, Rima

Submitted to: Journal of Medicinal Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 30, 2012
Publication Date: December 1, 2012
Citation: Fomovska, A., Wood, R., Mui, E., Welsh, W., Dubey, J.P., Ferreira, L.R., Hickman, M., Lee, P., Leed, S., Auschwitz, J., Sommerville, C., Woods, S., Roberts, C., Mcleod, R. 2012. Salicylanilide inhibitors of Toxoplasma gondii. Journal of Medicinal Chemistry. 55:8375-8391.

Interpretive Summary: Toxoplasma gondii is a single-celled parasite of all warm-blooded hosts worldwide. It causes mental retardation and loss of vision in children, and abortion in livestock. There is no effective, safe medicine to cure toxoplasmosis. Here, the authors report a new group of chemicals that show promise to treat toxoplasmosis. The results will be of interest to biologists, parasitologists, and public health workers.

Technical Abstract: Toxoplasma gondii (T. gondii) is an apicomplexan parasite that can cause eye disease, brain disease, and death, especially in congenitally infected and immunocompromised people. Novel medicines effective against both active and latent forms of the parasite are greatly needed. The current study focused on the discovery of such medicines by exploring a family of potential inhibitors whose anti-apicomplexan activity has not been previously reported. Initial screening efforts revealed that niclosamide, a drug approved for anthelmintic use, possessed promising activity in vitro against T. gondii. This observation inspired the evaluation of the activity of a series of salicylanilides and derivatives. Several inhibitors with activities in the nanomolar range with no appreciable in vitro toxicity to human cells were identified. An initial structure-activity relationship was explored. Four compounds were selected for evaluation in an in vivo model of infection, and two derivatives with potentially enhanced pharmacological parameters demonstrated the best activity profiles.

Last Modified: 10/31/2014