Discovery of new inhibitors of Toxoplasma gondii thanks to the Pathogen Box [PublishAheadOfPrint]

Toxoplasma gondii is a cosmopolitan protozoan parasite which affects approximately 30% of the population worldwide. The drugs currently used against toxoplasmosis are few in number and show several limitations, such as a drug intolerance, poor bioavailability or drug resistance mechanism developed by the parasite. Thus it is important to find new compounds able to inhibit parasite invasion or proliferation. In this study, the 400 compounds of the open access Pathogen Box provided by the Medicines for Malaria Venture (MMV) foundation were screened for their anti-Toxoplasma gondii activity. A preliminary in vitro screening performed over 72 hours by an enzyme-linked immunosorbent assay (ELISA) revealed fifteen interesting compounds that were effective against T. gondii at 1 μM. Their cytotoxicity was estimated on Vero cells and their 50% inhibitory concentration (IC₅₀) values were further calculated. As a result, eight anti-Toxoplasma gondii compounds with an IC₅₀ value lesser than 2 μM and a selectivity index (SI) value greater than 4 were identified. The most active was MMV675968, showing an IC₅₀ of 0.02 μM and a selectivity index value equal to 275. Two other compounds, MMV689480 and MMV687807, also showed a good activity against T. gondii with IC₅₀ values of 0.10 μM (SI = 86.6) and 0.15 μM (SI = 11.3), respectively. Structure-activity relationships for the eight selected compounds were also discussed on the basis of fingerprinting similarity measurements using the Tanimoto method. The anti-Toxoplasma gondii compounds highlighted here represent potential candidates for the development of new drugs that could be used against toxoplasmosis.

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