Abstract
The dihydroartemisinin-derived dimer (DHA dimer) was synthesized, and its antimalarial activities were evaluated both in vitro and in vivo. The dimer IC50 value of 0.51 ± 0.12 nM in vitro was significantly lower than that of DHA at 1.81 ± 0.70 nM. The dimer ED50 values were 0.44 ± 0.03 and 0.18 ± 0.03 mg/(kg·day) in vivo for intragastric (i.g.) and intravenous (i.v.) groups, respectively, to Plasmodium yoelii rodent malaria. It also performed better relative to those of DHA which had ED50 values of 0.76 ± 0.03 mg/(kg·day) (i.g.) and 0.32 ± 0.03 mg/(kg·day) (i.v.). Moreover, the recrudescence rate, negative conversion rate, and cure rate of the dimer showed superior performance. Furthermore, the metabolites and major metabolic pathways of the dimer in rats were preliminarily investigated using the HPLC-HRMSn method. Twenty-seven metabolites, including DHA, 11 metabolites of DHA, and 15 other novel metabolites, were detected in rats after i.g. administration of dimer. The metabolic pathways of the 15 novel metabolites were inferred: deoxygenation, hydroxylation, and hydroxylation with dehydration.
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Funding
The work was sponsored by the National Natural Science Foundation of China (Grant No. 81373364), the Fund for Shanxi Key Subjects Construction (FSKSC), the Applied Basic Research Project of Shanxi Province (201701D221162), and the Science and Technology Innovation Project of Higher School of Shanxi Province (2017148).
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Two hundred and fifty-six ICR male mice and 16 healthy SD rats were used in this study with the permission of the Ethics Committee of Shanxi Medical University (20160513).
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Dai H is now employed by Children’s Hospital of Shanxi (Women Health Center of Shanxi).
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Zhang, G., Dai, H., Ren, G. et al. Antimalarial activity and metabolism of dihydroartemisinin-derived dimer. Parasitol Res 117, 2243–2254 (2018). https://doi.org/10.1007/s00436-018-5911-x
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DOI: https://doi.org/10.1007/s00436-018-5911-x