Antimalarial activity of new dihydroartemisinin derivatives. 5. Sugar analogues1-4

Article abstract of DOI:10.1021/jm00087a021

A series of dihydroartemisinin derivatives containing a sugar moiety was prepared in the search for analogues with good water solubility and high antimalarial activity. The preparation of the new compounds were achieved by treatment of dihydroartemisinin (2) with chlorotrimethylsilane in pyridine solution at -10 °C to give a nearly quantitative yield of 10-O- (trimethylsilyl)dihydroartemisinin (3), which was then condensed with 1- hydroxypolyacetylated sugars 5 to give dihydroartemisinin derivatives 7a-d. Deacetylation of intermediates 7 gave the desired sugar derivatives 8. The resulting derivatives, tested in vitro against Plasmodium falciparum, were found to be more effective against W-2 than D-6 clones and were not cross- resistant with existing antimalarials. Trimethylsilylated compound 3 is more effective than derivatives 7a-d, which possess activity comparable to or better than that of artemisinin itself. Deacetylated compounds 8a-d were substantially less active than 7 in both cell lines. In P. berghei-infected mice, 7a-c showed 5/5, 2/5, and 3/5 cures, respectively, at 320 mg/kg per day x 3, whereas 7d showed no activity at the same dosage. However, 7d did prolong the life span in 3/5 of the infected mice at 640 mg/kg per day x 3 dose level. Trimethylsilylated compound 3 was also the most effective among the compounds studied, with 5/5 cures at 80 mg/kg per day x 3. The deacetylated sugar derivatives 8a-d showed only slight in vivo antimalarial activity.