The development of novel chemotherapeutic agents has become an urgent task
due to the development and rapid spread of drug resistance in Plasmodium fa
lciparum. the protozoan parasite responsible for cerebral malaria. Cyclin-d
ependent kinases (CDKs) are essential for the regulation of the eukaryotic
cell cycle, and several enzymes of this family have been identified in P. f
alciparum. In recent years, a number of purine-derived kinase inhibitors ha
ve been synthesised, some of which display selective activity against CDKs.
This report describes a study in which various purine derivatives were scr
eened for in vitro antimalarial activity. The erythrocytic asexual stages o
f the chloroquine-resistant P. falciparum strain (FCR-3) were cultivated in
vitro in the presence of the various purines, and their effect on parasite
proliferation was determined by the [H-3]hypoxanthine incorporation assay.
Our results show considerable variation in the sensitivity of P. falciparu
m to the different purines, as well as a general independence from their ef
fect on purified starfish CDK1/cyclin B activity, which has been the standa
rd assay used to identify CDK-specific inhibitors. Two subfamilies of purin
es with moderate to poor activity against CDK1/cyclin B activity showed sub
micromolar activity against P. falciparum. Structure-activity analysis indi
cates that certain structural features are associated with increased activi
ty against P. falciparum. These features can be exploited to synthesise com
pounds with higher activity and specificity towards P. falciparum. (C) 2001
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