ChloroquineV1, France, Analysis, bibRecord, 000377

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

Identifieur interne : 000377 ( France/Analysis ); précédent : 000376; suivant : 000378

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

Auteurs : Leonie Harmse [Afrique du Sud] ; Robyn Van Zyl [Afrique du Sud] ; Nathanael Gray [États-Unis] ; Peter Schultz [États-Unis] ; Sophie Leclerc [France] ; Laurent Meijer [France] ; Christian Doerig [France] ; Ivan Havlik [Afrique du Sud]

Source :

Biochemical Pharmacology [ 0006-2952 ] ; 2001.

RBID : ISTEX:9A5ACF2A691D8978BC3B7521E442FDE8D28344B2

English descriptors

KwdEn :
- Cyclin-dependent kinases, Kinase inhibitors, Malaria, Olomoucine, Plasmodium falciparum, Purvalanol, Roscovitine.
Teeft :
- Antimalarial, Antimalarial activity, Assay, Biochem, Biochemical pharmacology, Cdks, Compound, Cyclin, Derivative, Doerig, Enzyme, Enzyme system, Experimental details, Falciparum, Falciparum enzymes, Gametocyte, Gametocyte formation, Harmse, High activity, Inhibitor, Inhibitory effect, Isomer, Isopentenyladenine, Kinase, Kinase activity, Kinase inhibitors, Meijer, Olomoucine, Parasite, Parasite growth, Pharmacology, Plasmodium, Plasmodium falciparum, Plasmodium falciparum protein kinase, Protein kinase, Protein kinases, Purine, Purine derivatives, Purine ring, Purvalanol, Purvalanol series, Ring stage, Roscovitine, Structural comparison, Submicromolar, Substituent, Substitution, Unpublished observations, Various purine derivatives.

Abstract

Abstract: The development of novel chemotherapeutic agents has become an urgent task due to the development and rapid spread of drug resistance in Plasmodium falciparum, the protozoan parasite responsible for cerebral malaria. Cyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle, and several enzymes of this family have been identified in P. falciparum. In recent years, a number of purine-derived kinase inhibitors have been synthesised, some of which display selective activity against CDKs. This report describes a study in which various purine derivatives were screened for in vitro antimalarial activity. The erythrocytic asexual stages of 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 [3H]hypoxanthine incorporation assay. Our results show considerable variation in the sensitivity of P. falciparum to the different purines, as well as a general independence from their effect on purified starfish CDK1/cyclin B activity, which has been the standard assay used to identify CDK-specific inhibitors. Two subfamilies of purines with moderate to poor activity against CDK1/cyclin B activity showed submicromolar activity against P. falciparum. Structure-activity analysis indicates that certain structural features are associated with increased activity against P. falciparum. These features can be exploited to synthesise compounds with higher activity and specificity towards P. falciparum.

Url:

https://api.istex.fr/ark:/67375/6H6-XMF89QKX-B/fulltext.pdf

DOI: 10.1016/S0006-2952(01)00644-X

Affiliations:

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ISTEX:9A5ACF2A691D8978BC3B7521E442FDE8D28344B2

Le document en format XML

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<front><div type="abstract" xml:lang="en">Abstract: The development of novel chemotherapeutic agents has become an urgent task due to the development and rapid spread of drug resistance in Plasmodium falciparum, the protozoan parasite responsible for cerebral malaria. Cyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle, and several enzymes of this family have been identified in P. falciparum. In recent years, a number of purine-derived kinase inhibitors have been synthesised, some of which display selective activity against CDKs. This report describes a study in which various purine derivatives were screened for in vitro antimalarial activity. The erythrocytic asexual stages of 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 [3H]hypoxanthine incorporation assay. Our results show considerable variation in the sensitivity of P. falciparum to the different purines, as well as a general independence from their effect on purified starfish CDK1/cyclin B activity, which has been the standard assay used to identify CDK-specific inhibitors. Two subfamilies of purines with moderate to poor activity against CDK1/cyclin B activity showed submicromolar activity against P. falciparum. Structure-activity analysis indicates that certain structural features are associated with increased activity against P. falciparum. These features can be exploited to synthesise compounds with higher activity and specificity towards P. falciparum.</div>
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Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitro growth of Plasmodium falciparum

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

Source :

English descriptors

Abstract

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