2,6,9-Trisubstituted purines as CRK3 kinase inhibitors with antileishmanial activity in vitro.
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.
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.
Eva
E
Řezníčková
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.
Alexandr
A
Popa
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.
Tomáš
T
Gucký
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.
Marek
M
Zatloukal
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.
Libor
L
Havlíček
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.
Václav
V
Bazgier
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.
Karel
K
Berka
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.
Radek
R
Jorda
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.
Igor
I
Popa
Department of Microbiology and Molecular Genetics, IMRIC, Hebrew University-Hadassah Medical School, 9112102 Jerusalem, Israel.
Abdelmajeed
A
Nasereddin
Department of Microbiology and Molecular Genetics, IMRIC, Hebrew University-Hadassah Medical School, 9112102 Jerusalem, Israel.
Charles L
CL
Jaffe
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.
Vladimír
V
Kryštof
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.
Miroslav
M
Strnad
D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D007893:Leishmania donovani / Q000187:drug effects*; D018320:Leishmania major / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D050737:Proto-Oncogene Proteins c-crk / Q000037:antagonists & inhibitors*; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000981:Antiprotozoal Agents; D050737:Proto-Oncogene Proteins c-crk; D011687:Purines
Cyclin-dependent kinase; Inhibitor; Leishmania; Purine