| Summary: | Casein kinase II (CK2) is an intensively studied enzyme, involved in different diseases, cancer in particular. Different scaffolds were used to develop inhibitors of this enzyme. Here, we report on the synthesis and biological evaluation of twenty phenolic, ketonic, and <i>para</i>-quinonic indeno[1,2-<i>b</i>]indole derivatives as CK2 inhibitors. The most active compounds were 5-isopropyl-1-methyl-5,6,7,8-tetrahydroindeno[1,2-<i>b</i>]indole-9,10-dione <b>4h</b> and 1,3-dibromo-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-<i>b</i>]indole-9,10-dione <b>4w</b> with identical IC<sub>50</sub> values of 0.11 µM. Furthermore, the development of a QSAR model based on the structure of indeno[1,2-<i>b</i>]indoles was performed. This model was used to predict the activity of 25 compounds with naphtho[2,3-<i>b</i>]furan-4,9-dione derivatives, which were previously predicted as CK2 inhibitors via a molecular modeling approach. The activities of four naphtho[2,3-<i>b</i>]furan-4,9-dione derivatives were determined in vitro and one of them (<i>N</i>-isopentyl-2-methyl-4,9-dioxo-4,9-dihydronaphtho[2,3-<i>b</i>]furan-3-carboxamide) turned out to inhibit CK2 with an IC<sub>50</sub> value of 2.33 µM. All four candidates were able to reduce the cell viability by more than 60% after 24 h of incubation using 10 µM.
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