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Bioorg Med Chem Lett. 2015 Jun 1;25(11):2298-301. doi: 10.1016/j.bmcl.2015.04.030. Epub 2015 Apr 16.

2,6,9-Trisubstituted purines as CRK3 kinase inhibitors with antileishmanial activity in vitro.

Author information

1
Laboratory of Growth Regulators & Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 11, 783 71 Olomouc, Czech Republic.
2
Laboratory of Growth Regulators & Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 11, 783 71 Olomouc, Czech Republic; Department of Physical Chemistry, Faculty of Science, Palacký University, 17. listopadu 1192/12, 771 46 Olomouc, Czech Republic.
3
Department of Physical Chemistry, Faculty of Science, Palacký University, 17. listopadu 1192/12, 771 46 Olomouc, Czech Republic; Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University, 17. listopadu 1192/12, 771 46 Olomouc, Czech Republic.
4
Laboratory of Growth Regulators & Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 11, 783 71 Olomouc, Czech Republic; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Žlutý kopec 7, Brno 656 53, Czech Republic.
5
Laboratory of Growth Regulators & Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 11, 783 71 Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 779 00 Olomouc, Czech Republic; Department of Organic Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 771 46 Olomouc, Czech Republic.
6
Department of Microbiology and Molecular Genetics, IMRIC, Hebrew University-Hadassah Medical School, 9112102 Jerusalem, Israel.
7
Laboratory of Growth Regulators & Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 11, 783 71 Olomouc, Czech Republic. Electronic address: vladimir.krystof@upol.cz.

Abstract

Here we describe the leishmanicidal activities of a library of 2,6,9-trisubstituted purines that were screened for interaction with Cdc2-related protein kinase 3 (CRK3) and subsequently for activity against parasitic Leishmania species. The most active compound inhibited recombinant CRK3 with an IC50 value of 162 nM and was active against Leishmania major and Leishmania donovani at low micromolar concentrations in vitro. Its mode of binding to CRK3 was investigated by molecular docking using a homology model.

KEYWORDS:

Cyclin-dependent kinase; Inhibitor; Leishmania; Purine

PMID:
25937014
DOI:
10.1016/j.bmcl.2015.04.030
[Indexed for MEDLINE]

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