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

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Yuet WuRichard K Haynes

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....Continue Reading

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BETA
NMR
X-ray
column chromatography
biopsies

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SHELXTL PLUS
Gen5

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