Salicylanilide Inhibitors of Toxoplasma gondii

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• 作者：Alina Fomovska ; Richard D. Wood ; Ernest Mui ; Jitenter P. Dubey ; Leandra R. Ferreira ; Mark R. Hickman ; Patricia J. Lee ; Susan E. Leed ; Jennifer M. Auschwitz ; William J. Welsh ; Caroline Sommerville ; Stuart Woods ; Craig Roberts ; Rima McLeod
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 11, 2012
• 年：2012
• 卷：55
• 期：19
• 页码：8375-8391
• 全文大小：541K
• 年卷期：v.55,no.19(October 11, 2012)
• ISSN：1520-4804

文摘

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 antiapicomplexan 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鈥揳ctivity 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.