Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitro growth of Plasmodium falciparum

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 Elsevier Science Inc. All rights reserved.