Orally active, water-soluble antimalarial 3-aryltrioxanes: short synthesis and preclinical efficacy testing in rodents.
Short chemical syntheses of four new antimalarial trioxanes are presented, starting with inexpensive and commercially available cyclohexanone. Almost exclusive formation of the trioxane 12alpha-stereoisomers simplifies product purification. Carboxyphenyltrioxanes 3 and 5 are thermally stable in air even at 60 degrees C for 24 h. When administered orally, these new carboxyphenyltrioxanes are highly efficacious in curing malaria-infected mice. Important for their practical in vivo administration, these new synthetic antimalarial trioxanes 3 and 5 are 14-20 times more soluble in water at pH 7.4 than is artelinic acid (1), a leading semisynthetic, herb-derived antimalarial trioxane drug candidate.
Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 N. Charles Street, Baltimore, Maryland 21218-2685, USA. gposner1@hem.jhu.edu
Gary H
GH
Posner
Heung Bae
HB
Jeon
Poonsakdi
P
Ploypradith
Ik-Hyeon
IH
Paik
Kristina
K
Borstnik
Suji
S
Xie
Theresa A
TA
Shapiro
D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001584:Benzoxepins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010962:Plasmodium berghei; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C465456:12-benzyloxy-4-(4-carboxyphenyl)-2,3,13-trioxatricyclo(7.2.2.0(1,7))tridecane; D000962:Antimalarials; D001565:Benzoates; D001584:Benzoxepins; C465455:decahydro-3-(4-carboxyphenyl)-3,12-epoxy-12H-pyrano(4,3-j)-1,2-benzodioxepin