Antimalarial simplified 3-aryltrioxanes: synthesis and preclinical efficacy/toxicity testing in rodents.
A streamlined five-step chemical synthesis of rationally designed, simplified 3-aryltrioxane 8a is described. A noteworthy feature of this synthetic scheme is use of air rather than expensive molecular oxygen as the source of the pharmacologically critical peroxide unit in trioxane 8a. This simplified acetal trioxane carboxylic acid 8a is thermally stable, and it is hydrolytically stable in water even at 40 degrees C and pH 7.4 for at least 7 days. Preclinical evaluation of this water-soluble synthetic trioxane 8a in rodents shows it to have at least as good a therapeutic index (efficacy/toxicity) as that of water-soluble semisynthetic trioxane artelinic acid (5).
Posner
G H
GH
Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
Jeon
H B
HB
Parker
M H
MH
Krasavin
M
M
Paik
I H
IH
Shapiro
T A
TA
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D004356:Drug Storage; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
C435942:1-(4-carboxyphenyl)-3-methoxy-2,12,13-trioxatricyclo(7.2.2.0(4,9))tridecane; D000962:Antimalarials; D001565:Benzoates; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006575:Heterocyclic Compounds, 3-Ring