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. 2012 Oct 11;55(19):8375-91.
doi: 10.1021/jm3007596. Epub 2012 Sep 26.

Salicylanilide inhibitors of Toxoplasma gondii

Alina Fomovska  1 , 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
Affiliations

Salicylanilide inhibitors of Toxoplasma gondii

Alina Fomovska et al. J Med Chem. .

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.

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Conflict of interest statement

There are no conflicts of interest.

Figures

Figure 1
Figure 1
Inhibition of T. gondii RH-YFP fluorescence in the presence of Compounds 3i, 3j, 7a, 14a, 14b. FIBS, host fibroblasts alone, not infected; P/S, infected control treated with pyrimethamine and sulfadiazine in combination; RH-YFP, untreated infected fibroblast control; 0.1% DMSO (vehicle) infected fibroblast control; [nM], concentration of inhibitor dissolved in 0.1% DMSO. Ordinate axis: Relative Fluorescence Units.
Figure 2
Figure 2
Effect of Selected Compounds on Survival of HFF Cells. Ordinate: Optical Density.
Figure 3
Figure 3
Effect of various dosing conditions on prolonged survival of RH-YFP tachyzoites, measured by inhibition of RH-YFP fluorescence. Abscissa: 4 days, Condition A; 10 days, renewed at 4, Condition B; 10 days, Condition C; All time, Condition D. Ordinate: Relative Flourescence Units.
Figure 3
Figure 3
Effect of various dosing conditions on prolonged survival of RH-YFP tachyzoites, measured by inhibition of RH-YFP fluorescence. Abscissa: 4 days, Condition A; 10 days, renewed at 4, Condition B; 10 days, Condition C; All time, Condition D. Ordinate: Relative Flourescence Units.
Figure 4
Figure 4
Effect of Compound 14a (left panel) on survival in a mouse model following challenge with T. gondii oocysts of the Me-49 strain. On day 8, p<0.014. N= 5 per group. Doses 25 and 100 mg/kg (dose 25/100) are shown with a single line as both have the same results. Effect of Compound 14b (right panel) on survival in a mouse model following challenge with T. gondii oocysts of the TgGoatUS4 strain. On day 8, p<0.014. N=5 per group. Doses 25 and 100 mg/kg (dose 25/100) are shown with a single line as both have the same results.
Scheme 1
Scheme 1
Preparation of 3a – 3 ae.
Scheme 2
Scheme 2
Scheme 3
Scheme 3
Scheme 4
Scheme 4
Scheme 5
Scheme 5
See this image and copyright information in PMC

References

    1. McLeod R, Boyer K, Karrison T, Kasza K, Swisher C, Roizen N, Jalbrzikowski J, Remington J, Heydemann P, Noble AG, Mets M, Holfels E, Withers S’, Latkany P, Meier P. Outcome of treatment for congenital toxoplasmosis, 1981–2004: the National Collaborative Chicago-Based, Congenital Toxoplasmosis Study. Clin Infect Dis. 2006;42:1383–1394. - PubMed
    1. Roizen N, Kasza K, Karrison T, Mets M, Noble AG, Boyer K, Swisher C, Meier P, Remington J, Jalbrzikowski J, McLeod R, Kipp M, Rabiah P, Chamot D, Estes R, Cezar S, Mack D, Pfiffner L, Stein M, Danis B, Patel D, Hopkins J, Holfels E, Stein L, Withers S, Cameron A, Perkins J, Heydemann P. Impact of visual impairment on measures of cognitive function for children with congenital toxoplasmosis: implications for compensatory intervention strategies. Pediatrics. 2006;118:e379–390. - PubMed
    1. McLeod R, Khan AR, Noble GA, Latkany P, Jalbrzikowski J, Boyer K. Severe sulfadiazine hypersensitivity in a child with reactivated congenital toxoplasmic chorioretinitis. Pediatr Infect Dis J. 2006;25:270–272. - PubMed

    1. NDA #018669 (Bayer)

    1. Weinbach EC, Garbus J. Mechanism of action of reagents that uncouple oxidative phosphorylation. Nature. 1969;221:1016–1018. - PubMed

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