Salicylanilide inhibitors of toxoplasma gondii

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

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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-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.
LanguageEnglish
Pages8375-8391
Number of pages17
JournalJournal of Medicinal Chemistry
Volume55
Issue number19
DOIs
Publication statusPublished - 12 Sep 2012

Fingerprint

Toxoplasma
Salicylanilides
Parasites
Niclosamide
Anthelmintics
Brain Death
Eye Diseases
Brain Diseases
Structure-Activity Relationship
Pharmacology
Infection
Pharmaceutical Preparations
In Vitro Techniques
salicylanilide

Keywords

  • salicylanilide inhibitors
  • toxoplasma gondii
  • congenital toxoplasmosis
  • oocysts
  • mechanism

Cite this

Fomovska, A., Wood, R. D., Mui, E., Dubey, J. P., Ferreira, L. R., Hickman, M. R., ... Mcleod, R. (2012). Salicylanilide inhibitors of toxoplasma gondii. Journal of Medicinal Chemistry, 55(19), 8375-8391. https://doi.org/10.1021/jm3007596
Fomovska, Alina ; Wood, Richard D. ; Mui, Ernest ; Dubey, Jitenter P. ; Ferreira, Leandra R. ; Hickman, Mark R. ; Lee, Patricia J. ; Leed, Susan E. ; Auschwitz, Jennifer M. ; Welsh, William J. ; Sommerville, Caroline ; Woods, Stuart ; Roberts, Craig ; Mcleod, Rima. / Salicylanilide inhibitors of toxoplasma gondii. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 19. pp. 8375-8391.
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Fomovska, A, Wood, RD, Mui, E, Dubey, JP, Ferreira, LR, Hickman, MR, Lee, PJ, Leed, SE, Auschwitz, JM, Welsh, WJ, Sommerville, C, Woods, S, Roberts, C & Mcleod, R 2012, 'Salicylanilide inhibitors of toxoplasma gondii' Journal of Medicinal Chemistry, vol. 55, no. 19, pp. 8375-8391. https://doi.org/10.1021/jm3007596

Salicylanilide inhibitors of toxoplasma gondii. / Fomovska, Alina; Wood, Richard D.; Mui, Ernest; Dubey, Jitenter P.; Ferreira, Leandra R.; Hickman, Mark R.; Lee, Patricia J.; Leed, Susan E.; Auschwitz, Jennifer M.; Welsh, William J.; Sommerville, Caroline; Woods, Stuart; Roberts, Craig; Mcleod, Rima.

In: Journal of Medicinal Chemistry, Vol. 55, No. 19, 12.09.2012, p. 8375-8391.

Research output: Contribution to journalArticle

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AU - Woods, Stuart

AU - Roberts, Craig

AU - Mcleod, Rima

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Fomovska A, Wood RD, Mui E, Dubey JP, Ferreira LR, Hickman MR et al. Salicylanilide inhibitors of toxoplasma gondii. Journal of Medicinal Chemistry. 2012 Sep 12;55(19):8375-8391. https://doi.org/10.1021/jm3007596