Synthesis, Characterization, and Antimalarial Activity of the Glucuronides of the Hydroxylated Metabolites of Arteether

Abstract

The hydroxylated metabolites (log P 2.6-2.7) of β-arteether (1) in rat liver microsomes that retain their endoperoxide moiety showed comparable in vitro antimalarial activity to that of the parent drug arteether (log P = 3.89). The search for analogs of artemisinin (7) more suitable for intravenous use led to the synthesis of the glucuronide conjugates of the phase I hydroxylated metabolites of arteether which were found to have good water solubility, yet retained moderate lipophilicity (log P = 0.6-1.8). While a strong correlation was observed between the log Pvalue of the glucuronides, the phase I metabolites, and the parent compound, it was found that 9β-hydroxyarteetherglucuronide (26) was the most active and the most polar (log P = 0.61) of the glucuronides. While the in vitro antimalarial activity of 26 (IC50 = 89.3 ng/mL) was found to be much less than that for the parent compound, the activity of 26 was within a range that would have potential therapeutic use. © 1995, American Chemical Society. All rights reserved.