title: Several human cyclin-dependent kinase inhibitors, structurally related to roscovitine, are new anti-malarial agents.
abstract: 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.
authors.affiliation: Laboratoire de Parasitologie, CNR du Paludisme, AP-HP, Hôpital Bichat & UMR 216 IRD, Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Pharmaceutiques, 4 avenue de l'Observatoire, Paris 75006, France. sandrine.houze@bch.aphp.fr.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Houzé
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints-Pères, Paris 75270, France. luc.demange@parisdescartes.fr.
authors.forename: Nha-Thu
authors.initials: NT
authors.lastname: Hoang
authors.affiliation: Protein Phosphorylation and Human Diseases Group, CNRS, USR 3151, Station biologique, Roscoff 29680, France. olivier.lozach@sb-roscoff.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.affiliation: Laboratoire de Parasitologie, CNR du Paludisme, AP-HP, Hôpital Bichat & UMR 216 IRD, Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Pharmaceutiques, 4 avenue de l'Observatoire, Paris 75006, France. jacques.lebras@bch.aphp.fr.
authors.forename: Jacques
authors.initials: J
authors.lastname: Le Bras
authors.affiliation: Protein Phosphorylation and Human Diseases Group, CNRS, USR 3151, Station biologique, Roscoff 29680, France. herve.galons@parisdescartes.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: ManRos Therapeutics, Hôtel de Recherche, Centre de Perharidy, Roscoff 29680, France. herve.galons@parisdescartes.fr.
authors.forename: Hervé
authors.initials: H
authors.lastname: Galons
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints-Pères, Paris 75270, France. luc.demange@parisdescartes.fr.
authors.forename: Luc
authors.initials: L
authors.lastname: Demange
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology; D000077546:Roscovitine; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000962:Antimalarials; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases