Synthesis and evaluation of mycophenolic acid derivatives as potential anti-Toxoplasma gondii agents
Nineteen mycophenolic acid (MPA) derivatives were designed and synthesized, and their anti- Toxoplasma activity evaluated for the first time. Among them, N -propylimidazole-modified compound E5 demonstrated the strongest activity, and the IC 50 against HFF-1 (Human Foreskin Fibroblasts-1) cells following infection with T. gondii is 80.9 μM (MPA-211.5 μM) and its selectivity index is 2.2 (MPA-1.2). In vivo experiments, E5 can significantly inhibit the proliferation of tachyzoites in the abdominal cavity of mice acutely infected with T. gondii (inhibition rates 46.7%), and this inhibitory effect was greater than that of spiramycin (inhibition rates 31.3%) and MPA (inhibition rates 15.9%), this indicated that E5 had significant protective effects on the host during acute Toxoplasma infection. In addition, E5 can reduce the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum of infected mice, significantly increase the level of glutathione (GSH) in the liver, and significantly reduce the level of malondialdehyde (MDA), indicating that it has a hepatoprotective effect against T. gondii infection. Similarly, E5 can relieve hepatomegaly and splenomegaly induced by acute Toxoplasma infection. Spiramycin aggravated appetite loss in infected mice, while E5 did not. In summary, the results indicated that E5 has potential as a candidate anti- T. gondii drug.
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