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Molecules 2018, 23(7), 1713; https://doi.org/10.3390/molecules23071713

Facile Preparation of N-Glycosylated 10-Piperazinyl Artemisinin Derivatives and Evaluation of Their Antimalarial and Cytotoxic Activities

1
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
2
Department of Biomedical, Surgical and Dental Sciences (DiSBIOC), University of Milan, Via Pascal 36, 20133 Milan, Italy
3
Department of Pharmacological & Biomolecular Sciences (DiSFeB), University of Milan, Via Pascal 36, 20133 Milan, Italy
4
Center of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom 2520, South Africa
5
Inter University Center for Malaria Research, Italian Malaria Network, University of Perugia, 06100 Perugia, Italy
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 19 June 2018 / Revised: 6 July 2018 / Accepted: 10 July 2018 / Published: 13 July 2018
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Abstract

According to the precepts that C-10 amino-artemisinins display optimum biological activities for the artemisinin drug class, and that attachment of a sugar enhances specificity of drug delivery, polarity and solubility so as to attenuate toxicity, we assessed the effects of attaching sugars to N-4 of the dihydroartemisinin (DHA)-piperazine derivative prepared in one step from DHA and piperazine. N-Glycosylated DHA-piperazine derivatives were obtained according to the Kotchetkov reaction by heating the DHA-piperazine with the sugar in a polar solvent. Structure of the D-glucose derivative is secured by X-ray crystallography. The D-galactose, L-rhamnose and D-xylose derivatives displayed IC50 values of 0.58–0.87 nM against different strains of Plasmodium falciparum (Pf) and selectivity indices (SI) >195, on average, with respect to the mouse fibroblast WEHI-164 cell line. These activities are higher than those of the amino-artemisinin, artemisone (IC50 0.9–1.1 nM). Notably, the D-glucose, D-maltose and D-ribose derivatives were the most active against the myelogenous leukemia K562 cell line with IC50 values of 0.78–0.87 µM and SI > 380 with respect to the human dermal fibroblasts (HDF). In comparison, artemisone has an IC50 of 0.26 µM, and a SI of 88 with the same cell lines. Overall, the N-glycosylated DHA-piperazine derivatives display antimalarial activities that are greatly superior to O-glycosides previously obtained from DHA. View Full-Text
Keywords: artemisinins; artemisone; piperazine; N-glycosides; antimalarial activities; anti-tumour activities artemisinins; artemisone; piperazine; N-glycosides; antimalarial activities; anti-tumour activities
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Wu, Y.; Parapini, S.; Williams, I.D.; Misiano, P.; Wong, H.N.; Taramelli, D.; Basilico, N.; Haynes, R.K. Facile Preparation of N-Glycosylated 10-Piperazinyl Artemisinin Derivatives and Evaluation of Their Antimalarial and Cytotoxic Activities. Molecules 2018, 23, 1713.

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