Lipophilic Pyrimethamine analogs with anti-toxoplasmosis activity

Toxoplasmosis remains a threat for neonates and immuno-compromised populations, against which only broad spectrum antiparasitic drugs are currently available. Here, a virtual screen was conducted on a Plasmodium falciparum DHFR inhibitor library to identify novel Toxoplasma gondii DHFR inhibitors. Three hit compounds were identified, showing nM-range in vitro activity against T. gondii and high selectivity compared to mammalian cells. All compounds are highly lipophilic. However, the most promising compounds, P12 and P33 , did not exhibit significantly lower parasite burden of RH- T. gondii from infected mice in a 4-day suppressive test. Although P33 -treated mice appeared to have longer median survival time compared to vehicle control group, the survival time was still shorter than the survival time in the pyrimethamine-treated group. Nonetheless, the promising activity of our compounds can guide further anti-toxoplasmosis drug development.