Department of Parasitology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China; China-Africa Research Center of Infectious Diseases, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China.
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Eur J Med Chem. 2022 Apr 15;234:114244. doi: 10.1016/j.ejmech.2022.114244. Epub 2022 Mar 5.
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 (R = 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.
由于传统弓形虫病治疗方法存在诸多副作用，因此迫切需要开发高效低毒的新型抗弓形虫药物。本研究以药食同源的查尔酮骨架为先导化合物，设计合成了 6 个系列的查尔酮衍生物，其中近 1/2 的化合物在体外具有良好的抗弓形虫活性。采用随机森林法（R=0.9407）建立了第二批化合物抗弓形虫活性的定量构效关系模型。查尔酮分子骨架中的迈克尔受体在提高活性方面起着重要作用。在这些化合物中，有 4 个查尔酮衍生物在体外表现出较强的抗弓形虫活性和较低的细胞毒性。具体来说，其中 3 个（4a、4c 和 5e）能有效抑制弓形虫速殖子在体内的增殖。这 3 个查尔酮衍生物还显著降低了肝脾指数和丙氨酸转氨酶、天冬氨酸转氨酶和丙二醛等生化参数，提示它们对感染弓形虫速殖子的小鼠肝脏具有保护作用。总的来说，本文为开发抗弓形虫药物提供了一系列有前景的化合物。
