Evaluation of ursolic acid derivatives with potential anti-Toxoplasma gondii activity

• Published in: Experimental parasitology 2020-09, Vol.216, p.107935, Article 107935
• Main Authors: Zhang, Lin-Hao, Jin, Li-Li, Liu, Fang, Jin, Chunmei, Jin, Chun-Mei, Wei, Zhi-Yu
• Format: Article
• Language: English
• Subjects: Alanine Transaminase - blood; Animals; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacology; Anti-Infective Agents - therapeutic use; Anti-T. gondii; Aspartate Aminotransferases - blood; Coccidiostats - chemistry; Coccidiostats - pharmacology; Disease Models, Animal; Docking; Female; Glutathione - metabolism; in vitro; in vivo; Liver - drug effects; Liver - enzymology; Liver - pathology; Malondialdehyde - metabolism; Mice; Molecular Docking Simulation; Organ Size - drug effects; Protein Kinase Inhibitors - pharmacology; Protein Kinases; Random Allocation; Spiramycin - pharmacology; Spleen - drug effects; Spleen - pathology; TgCDPK1 inhibitors; Toxoplasma - drug effects; Toxoplasmosis - drug therapy; Toxoplasmosis, Animal - drug therapy; Triterpenes - chemistry; Triterpenes - pharmacology; Triterpenes - therapeutic use; Ursolic Acid
• ISSN: 0014-4894; 1090-2449
• DOI: 10.1016/j.exppara.2020.107935

Toxoplasma gondii is an important pathogen that causes serious public health problems. Currently, therapeutic drugs for toxoplasmosis cause serious side effects, and more effective and novel substances with relatively low toxicity are urgently needed. Ursolic acid (UA) has many properties that can be beneficial to healthcare. In this study, we synthesized eight series of UA derivatives bearing a tetrazole moiety and evaluated their anti-T. gondii activity in vitro using spiramycin as a positive control. Most of the synthesized derivatives exhibited better anti-T. gondii activity in vitro than UA, among which compound 12a exhibited the most potent anti-T. gondii activity. Furthermore, the results of biochemical parameter determination indicated that 12a effectively restored the normal body weight of mice infected with T. gondii, reduced hepatotoxicity, and exerted significant anti-oxidative effects compared with the findings for spiramycin. Additionally, our molecular docking study indicated that the synthesized compounds could act as potential inhibitors of T. gondii calcium-dependent protein kinase 1 (TgCDPK1), with 12a possessing strong affinity for TgCDPK1 via binding to the key amino acids GLU129 and TYR131. [Display omitted] •The synthesized ursolic acid derivatives bearing tetrazole moieties were evaluated for their anti-T. gondii activities.•Compound 12a is a promising hit for the development of new anti-T. gondii agents.•The investigation of the mechanism in vivo and binding mode of action of 12a to TgCDPK1 was performed.