Novel endoperoxide antimalarials: synthesis, heme binding, and antimalarial activity.
We report the synthesis of a series of novel epoxy endoperoxide compounds that can be prepared in high yields in one to three steps from simple starting materials. Some of these compounds inhibit the growth of Plasmodium falciparum in vitro. Structure-activity studies indicate that an endoperoxide ring bisubstituted with saturated cyclic moieties is the pharmacophore. To study the molecular basis of the action of these novel antimalarial compounds, we examined their ability to interact with oxidized and reduced forms of heme. Some of the compounds interact with oxidized heme in a fashion similar to chloroquine and other 4-aminoquinolines, while some of the compounds interact with reduced heme. However, the level of antimalarial potency is not well correlated with these activities, suggesting that some of the endoperoxides may exert their antimalarial activities by a novel mechanism of action.
Taylor
Dennis K
DK
Department of Chemistry, Adelaide University, South Australia, 5005, Australia. dennis.taylor@adelaide.edua.u
Avery
Thomas D
TD
Greatrex
Ben W
BW
Tiekink
Edward R T
ER
Macreadie
Ian G
IG
Macreadie
Peter I
PI
Humphries
Adam D
AD
Kalkanidis
Martha
M
Fox
Emma N
EN
Klonis
Nectarios
N
Tilley
Leann
L
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006418:Heme / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D010545:Peroxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
D000962:Antimalarials; D010545:Peroxides; D006418:Heme