Structure-activity relationships of lactone ring-opened analogs of the antimalarial 1,2,4-trioxane artemisinin.
1,2,4-Trioxane benzylic ethers 8a-e were prepared as simplified, tricyclic versions of the clinically used tetracyclic antimalarial drug artemisinin (1). Five additional artemisinin analogs (9-11) were prepared. Neither water solubility (analogs 8e and 11b) nor chelating ability (analogs 9 and 10), however, produced trioxanes of especially high in vitro antimalarial activity. Trioxane fluorobenzyl ether 8b is the most active in this series (more active than artemisinin) against Plasmodium falciparum parasites in vitro, with substantial activity also in mice infected with Plasmodium berghei parasites and with 10 times higher activity than artemisinin (1) in killing immature P. falciparum gametocytes.
Posner
G H
GH
Department of Chemistry, School of Arts and Sciences, Johns Hopkins University, Baltimore, Maryland 21218.
McGarvey
D J
DJ
Oh
C H
CH
Kumar
N
N
Meshnick
S R
SR
Asawamahasadka
W
W
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D037621:Artemisinins; D007783:Lactones / Q000737:chemistry; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000962:Antimalarials; D037621:Artemisinins; D007783:Lactones; D012717:Sesquiterpenes; C031327:artemisinin