Taylor, Dennis K

Avery, Thomas D

Tilley, Leann

Greatrex, Ben

Tiekink, Edward R T

Macreadie, Ian G

Macreadie, Peter I

Humphries, Adam D

Kalkanidis, Martha

Fox, Emma N

Klonis, Nectarios

2004

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.

Journal of Medicinal Chemistry, 47(7), p. 1833-1839

1520-4804

0022-2623

https://hdl.handle.net/1959.11/15500

en

American Chemical Society

Novel Endoperoxide Antimalarials: Synthesis, Heme Binding, and Antimalarial Activity

Journal Article

Publication