title: 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 beta-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 P value of the glucuronides, the phase I metabolites, and the parent compound, it was found that 9 beta-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.
authors.affiliation: Department of Medicinal Chemistry, University of Mississippi, University 38677, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ramu
authors.forename: J K
authors.initials: JK
authors.lastname: Baker
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D037621:Artemisinins; D002851:Chromatography, High Pressure Liquid; D005965:Glucuronates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D006868:Hydrolysis; D006900:Hydroxylation; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D010963:Plasmodium falciparum / Q000187:drug effects; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D005965:Glucuronates; D012717:Sesquiterpenes; C039060:artenimol; C055141:artemotil