Design, synthesis, derivatization, and structure-activity relationships of simplified, tricyclic, 1,2,4-trioxane alcohol analogues of the antimalarial artemisinin.
Novel C4-(hydroxyalkyl)trioxanes 5d and 5e were designed and synthesized based on an understanding of the molecular mechanism of action of similar 1,2,4-trioxanes structurally related to the antimalarial natural product artemisinin (1). In vitro efficacies of these two new pairs of C4-diastereomers against chloroquine-sensitive Plasmodium falciparum support conclusions about the importance to antimalarial activity of formation of a C4 radical by a 1,5-hydrogen atom abstraction. Derivatives 6, 7, and 21 of C4 beta-substituted trioxane alcohols 4a, 5d, and 5e were prepared, each in a single-step, high-yielding transformation. Four of these new analogues, 6a-c and 7, are potent in vitro antimalarials, having 140 to 50% of the efficacy of the natural trioxane artemisinin (1).
Cumming
J N
JN
Department of Chemistry, School of Arts and Sciences, Johns Hopkins University, Baltimore, Maryland 21218, USA.
Wang
D
D
Park
S B
SB
Shapiro
T A
TA
Posner
G H
GH
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D037621:Artemisinins; D002738:Chloroquine / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D012717:Sesquiterpenes / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000962:Antimalarials; D037621:Artemisinins; D006571:Heterocyclic Compounds; D012717:Sesquiterpenes; D002738:Chloroquine; C031327:artemisinin