Synthesis, in vitro and in vivo biological evaluation of dihydroartemisinin derivatives with potential anti-Toxoplasma gondii agents.

In this study, four series of dihydroartemisinin derivatives were designed, synthesized, and evaluated for anti-toxoplasma gondii activity, and calculated the selectivity index (SI). It was the higher the SI, the better the effect of this compound against Toxoplasma gondii. Our goal was to filter out compounds that were bigger SI than the lead compound. The compound with the highest SI was selected for the anti-toxoplasmosis test in mice in vivo. Among the synthesized compounds, the (3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyl-decahydro-12H-3,12-epoxy[1,2]di-oxepino[4,3 -i]isochromen-10-yl-(te-rt-butoxycarbonyl)-l-alaninate (A2) exhibited the most potent anti-T. gondii activity and low cytotoxicity (SI: 6.44), yielding better results than the lead compound DHA (SI: 1.00) and the clinically used positive-control drug spiramycin (SI: 0.72) in vitro. Furthermore, compound A2 had better growth inhibitory effects on T. gondii in vivo than spiramycin did and significantly reduced the number of tachyzoites in the peritoneal cavity of mice (P < 0.01). The evaluation of the data generated in the T. gondii mouse infection model indicates that compound A2 treatment was a good inhibitor of T. gondii in vivo and that it was effective in relieving the liver damage induced by T. gondii. In addition, the results of a docking study revealed that A2 could become a better T. gondii calcium-dependent protein kinase1 (TgCDPK1) inhibitor. For this reason, compound A2 has potential as an anti-parasitic drug. Further studies are required to elucidate the mechanism of the action of compound A2, as well as to develop drug delivery systems for patients.
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