Salicylanilide Inhibitors of Toxoplasma gondii
| Autor: | Jitenter P. Dubey, Caroline Sommerville, Craig W. Roberts, Mark Hickman, Ernest Mui, Leandra R. Ferreira, Jennifer M. Auschwitz, William J. Welsh, Rima McLeod, Richard D. Wood, Alina Fomovska, Stuart Woods, Patricia J. Lee, Susan E. Leed |
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| Rok vydání: | 2012 |
| Předmět: |
Plasmodium falciparum
Drug Resistance Mice Transgenic Drug resistance Pharmacology Salicylanilides Article Antimalarials Mice Structure-Activity Relationship In vivo parasitic diseases Drug Discovery medicine Animals Humans Cells Cultured Niclosamide Antiparasitic Agents biology Toxoplasma gondii Fibroblasts biology.organism_classification medicine.disease Antiparasitic agent Virology Toxoplasmosis Molecular Medicine Female Toxoplasma medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 55:8375-8391 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm3007596 |
| Popis: | Toxoplasma gondii(T. gondii) is an apicomplexan parasite that can cause eye disease, brain disease, and death, especially in congenitally infected and immune-compromised 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. |
| Databáze: | OpenAIRE |
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