ABSTRACT
Identification of new small molecules inhibiting protein kinase CK2 is highly required for the study of this protein's functions in cell and for the further development of novel pharmaceuticals against a variety of disorders associated with CK2 activity. In this article, a virtual screening of a random small-molecule library was performed and 12 compounds were initially selected for biochemical tests toward CK2. Among them, the most active compound 1 ([Formula: see text]) belonged to dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-4-ones. The complex of this compound with CK2 was analyzed, and key ligand-enzyme interactions were determined. Then, a virtual screening of 231 dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-4-one derivatives was performed and 37 compounds were chosen for in vitro testing. It was found that 32 compounds inhibit CK2 with [Formula: see text] values from 2.5 to 7.5 [Formula: see text]. These results demonstrate that dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-4-one is a novel class of CK2 inhibitors.
Subject(s)
Casein Kinase II/antagonists & inhibitors , Drug Design , Imidazoles/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Casein Kinase II/chemistry , Casein Kinase II/metabolism , Ligands , Molecular Docking Simulation , Protein Conformation , Protein Kinase Inhibitors/metabolism , Pyrimidines/metabolism , Structure-Activity RelationshipABSTRACT
Multicomponent reactions involving polyfunctional 4-amino-5-carboxamido-1,2,3-triazole and cyclic carbonyl-containing CH-acids were studied under conventional thermal heating, microwave and ultrasonic irradiation. The features of the reactions studied were discussed and the optimized procedures for the synthesis of final triazolopyrimidines were elaborated. In contrast to the similar MCRs of numerous other aminoazoles, a change of direction of the heterocyclizations in the case of 4-amino-5-carboxamido-1,2,3-triazole was not observed when microwave or thermal heating was substituted by ultrasonication at ambient temperature.
ABSTRACT
Representative benzimidazopyrimidinones were previously reported to be intercalating antitumor agents. In this work, we used 2-substituted 4,10-dihydrobenzo [4,5]imidazo[1,2-alpha]pyrimidin-4-ones for their diversification by regioselective alkylation. Under the conditions established, the alkylation gave 10-alkyl derivatives which permitted the parallel generation of a 500-member library of the title compounds.
