We report on the synthesis, activity testing, docking, and quantum mechanical scoring of novel imidazo[1,2-c]pyrimidin-5(6H)-one scaffold for cyclin-dependent kinase 2 (CDK2) inhibition. A series of 26 compounds substituted with aromatic moieties at position 8 has been tested in in vitro enzyme assays and shown to inhibit CDK2. 2D structure-activity relationships have ascertained that small substituents at position 8 (up to the size of naphtyl or methoxyphenyl) generally lead to single-digit micromolar IC50 values, whereas bigger substituents (substituted biphenyls) decreased the compounds' activities. The binding modes of the compounds obtained using Glide docking have exhibited up to 2 hinge-region hydrogen bonds to CDK2 and differed in the orientation of the inhibitor core and the placement of the 8-substituents. Semiempirical quantum mechanics-based scoring identified probable favourable binding modes, which will serve for future structure-based design and synthetic optimization of substituents of the heterocyclic core. In summary, we have identified a novel core for CDK2 inhibition and will explore it further to increase the potencies of the compounds and also monitor selectivities against other protein kinases.

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague 6 Czech Republic Regional Centre of Advanced Technologies and Materials Department of Physical Chemistry Palacký University Olomouc Czech Republic

Laboratory of Growth Regulators Centre of the Region Haná for Biotechnological and Agricultural Research Faculty of Science Palacký University and Institute of Experimental Botany Olomouc Czech Republic

Research Institute for Organic Syntheses Pardubice Rybitví Czech Republic Department of Organic Chemistry Faculty of Science Palacký University Olomouc Czech Republic

Research Institute for Organic Syntheses Pardubice Rybitví Czech Republic Faculty of Science University of Hradec Králové Hradec Králové Czech Republic

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