J Med Chem. 2012 Sep 12. [Epub ahead of print]
Salicylanilide Inhibitors of Toxoplasma gondii.
Fomovska A, Wood RD, Mui E, Dubey JP, Ferriera LR, Hickman MR, Lee PJ, Leed SE, Auschwitz JM, Welsh WJ, Sommerville C, Woods S, Roberts CW, McLeod R.
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 anti-helmintic 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.