Several Human Cyclin-Dependent Kinase Inhibitors, Structurally Related to Roscovitine, As New Anti-Malarial Agents
| Autor: | Olivier Lozach, Laurent Meijer, Hervé Galons, Jacques Le Bras, Nha-Thu Hoang, Sandrine Houzé, Luc Demange |
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| Rok vydání: | 2014 |
| Předmět: |
Purine
Spectrometry Mass Electrospray Ionization Magnetic Resonance Spectroscopy Anti malarial 2 6 9-trisubstituted purines Plasmodium falciparum cyclin-dependent kinases CDKs PfCDKs roscovitine Buchwald-Hartwig amination Pharmaceutical Science Article Cyclin-Dependent Kinase Inhibitors Analytical Chemistry lcsh:QD241-441 Antimalarials chemistry.chemical_compound lcsh:Organic chemistry Cyclin-dependent kinase parasitic diseases Drug Discovery Roscovitine medicine Ic50 values Humans Physical and Theoretical Chemistry Protein Kinase Inhibitors biology Kinase Organic Chemistry medicine.disease biology.organism_classification Virology Cyclin-Dependent Kinases chemistry Purines Chemistry (miscellaneous) biology.protein Molecular Medicine Malaria |
| Zdroj: | Molecules; Volume 19; Issue 9; Pages: 15237-15257 Molecules Molecules, Vol 19, Iss 9, Pp 15237-15257 (2014) |
| ISSN: | 1420-3049 |
| Popis: | In Africa, malaria kills one child each minute. It is also responsible for about one million deaths worldwide each year. Plasmodium falciparum, is the protozoan responsible for the most lethal form of the disease, with resistance developing against the available anti-malarial drugs. Among newly proposed anti-malaria targets, are the P. falciparum cyclin-dependent kinases (PfCDKs). There are involved in different stages of the protozoan growth and development but share high sequence homology with human cyclin-dependent kinases (CDKs). We previously reported the synthesis of CDKs inhibitors that are structurally-related to (R)-roscovitine, a 2,6,9-trisubstituted purine, and they showed activity against neuronal diseases and cancers. In this report, we describe the synthesis and the characterization of new CDK inhibitors, active in reducing the in vitro growth of P. falciparum (3D7 and 7G8 strains). Six compounds are more potent inhibitors than roscovitine, and three exhibited IC50 values close to 1 µM for both 3D7 and 7G8 strains. Although, such molecules do inhibit P. falciparum growth, they require further studies to improve their selectivity for PfCDKs. |
| Databáze: | OpenAIRE |
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