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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2018-07, Vol.23 (7), p.1713
• Main Authors: Wu, Yuet, Parapini, Silvia, Williams, Ian D, Misiano, Paola, Wong, Ho Ning, Taramelli, Donatella, Basilico, Nicoletta, Haynes, Richard K
• Format: Article
• Language: English
• Subjects: anti-tumour activities; antimalarial activities; Artemisinin; artemisinins; artemisone; Bioavailability; Crystallography; Cytotoxicity; D-Galactose; D-Ribose; Dihydroartemisinin; Drug delivery; Drug delivery systems; Galactose; Glucose; Glycosides; L-Rhamnose; Leukemia; Malaria; Maltose; Metabolism; Metabolites; Myeloid leukemia; N-glycosides; Neurotoxicity; Oxidative stress; Parasites; Pharmacokinetics; Physiology; Piperazine; Plasma; Polarity; Rhamnose; Ribose; Skin; Sugar; Toxicity; X-ray crystallography; Xylose
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules23071713

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. -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 IC values of 0.58⁻0.87 nM against different strains of ( ) 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 (IC 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 IC values of 0.78⁻0.87 µM and SI > 380 with respect to the human dermal fibroblasts (HDF). In comparison, artemisone has an IC of 0.26 µM, and a SI of 88 with the same cell lines. Overall, the -glycosylated DHA-piperazine derivatives display antimalarial activities that are greatly superior to -glycosides previously obtained from DHA.