Abstract
ABSTRACTToxoplasma 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 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 h by an enzyme-linked immunosorbent assay (ELISA) revealed 15 interesting compounds that were effective against T. gondii at 1 μM. Their cytotoxicity was estimated on Vero cells, and their 50% inhibitory concentrations (IC50) were further calculated. As a result, eight anti-Toxoplasma gondii compounds with an IC50 of less than 2 μM and a selectivity index (SI) value of 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 IC50s of 0.10 μM (SI of 86.6) and 0.15 μM (SI of 11.3), respectively. Structure-activity relationships for the eight selected compounds also were 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.
Highlights
Toxoplasma gondii is a cosmopolitan protozoan parasite which affects approximately 30% of the population worldwide
The 15 compounds reported in Table 1 demonstrated significant antiparasitic activity, as revealed by their ability to inhibit at least 50% of T. gondii growth at 1 M
We found that CC50 values ranged from 1.69 M to 15.92 M, depending on the compound we tested (Table 2)
Summary
Toxoplasma gondii is a cosmopolitan protozoan parasite which affects approximately 30% of the population worldwide. Toxoplasmosis is one of the most important parasitic diseases worldwide It is caused by the protozoan Toxoplasma gondii and affects approximately 25 to 30% of the world population [1]. Treatment of toxoplasmic encephalitis and chorioretinitis by these drugs can fail due to intolerance, poor absorption of these molecules [4, 5], or parasite resistance [6, 7] For these reasons, it is very important to search for new active compounds against toxoplasmosis. MMV has provided the biological activity of compounds from screening platforms (ChEMBL-NTD; https:// www.ebi.ac.uk/chemblntd), the plate layout, and compounds details (structures, trivial names, salt forms, and cLogP) These data can be found in an Excel spreadsheet, referred to as the Pathogen Box supporting information (https://www.pathogenbox .org/about-pathogen-box/supporting-information). The Pathogen Box is a powerful tool that could lead to the synthesis of new active molecules based on the structures of its compounds and improve the therapeutic armamentarium
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