Location: Animal Parasitic Diseases LaboratoryTitle: Salicylanilide inhibitors of Toxoplasma gondii
|FOMOVSKA, ALINA - University Of Chicago|
|WOOD, RICHARD - University Of Medicine And Dentistry Of New Jersey|
|MUI, ERNST - University Of Chicago|
|WELSH, WILLIAM - University Of Chicago|
|FERREIRA, LEANDRA - Collaborator|
|HICKMAN, MARK - Walter Reed Army Institute|
|LEE, PATRICIA - Walter Reed Army Institute|
|LEED, SUSAN - Walter Reed Army Institute|
|AUSCHWITZ, JENNIFER - Walter Reed Army Institute|
|SOMMERVILLE, CAROLINE - University Of Strathclyde|
|WOODS, STUART - University Of Strathclyde|
|ROBERTS, CRAIG - University Of Strathclyde|
|MCLEOD, RIMA - University Of Chicago|
Submitted to: Journal of Medicinal Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/30/2012
Publication Date: 12/1/2012
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.