Discovery and evaluation of chalcone derivatives as novel potential anti-Toxoplasma gondii agents

Abstract

Due to numerous side effects of traditional treatments for toxoplasmosis, it is urgent to develop new anti-Toxoplasma agents with high efficiency and low toxicity. In this study, using drug-food-homologous chalcone skeleton as a leading compound, 6 series of chalcone derivatives were designed, synthesized, and almost 1/2 compounds have good anti-Toxoplasma activity in vitro. The quantitative structure-activity relationship model of the anti-Toxoplasma activity of the second batch of compounds was established by random forest method (R2 = 0.9407). The Michael receptor in the molecular skeleton of chalcones plays an important role in improving the activity. Among these compounds, four chalcone derivatives exhibited potent anti-T. gondii activity and low cytotoxicity in vitro. Specifically, three of them (4a, 4c and 5e) effectively inhibited the proliferation of Toxoplasma tachyzoites in vivo. Liver and spleen index and biochemical parameters, such as alanine aminotransferase, aspartate aminotransferase and malondialdehyde were significantly decreased by the three chalcone derivatives, suggesting that they have protective effects on the liver of mice infected with Toxoplasma tachyzoites. Overall, this article provides a series of promising compounds for the development of anti-Toxoplasma agents.