Triazole and benzotriazole derivatives as novel inhibitors for p90 ribosomal S6 protein kinase 2: Synthesis, molecular docking and SAR analysis

A series of triazole and benzotriazole derivatives as novel p90 ribosomal S6 protein kinase 2 (RSK2) inhibitors were designed and synthesized. The in vitro activities against RSK2 were evaluated, and among 14 compounds, compounds 5, 6, 11, 12, 13 and 14 exhibited enzyme IC₅₀ values of 8.91, 2.86, 3.19, 3.05, 4.49 and 2.09 μmol/L respectively. The proposed binding modes were simulated using molecular docking method, and the docking results coupled with the structure-activity relationship (SAR) analysis indicated that all these active compounds bound to the RSK2 ATP binding site at NTKD, and the electron-donating groups on the 4-position of phenyl were the determinant point for the inhibitory activity. In the present study, a series of triazole and benzotriazole derivatives as novel p90 ribosomal S6 protein kinase 2 (RSK2) inhibitors were designed and synthesized. The in vitro activities of the 14 compounds against RSK2 were evaluated, among which, compounds 5, 6, 11, 12, 13 and 14 exhibited enzyme IC₅₀ values of 8.91, 2.86, 3.19, 3.05, 4.49 and 2.09 μmol/L respectively. The proposed binding modes were simulated using molecular docking method, and the docking results coupled with the structure-activity relationship (SAR) analysis indicated that all our active compounds bound to the RSK2 ATP binding site at NTKD, and the electron-donating groups on the 4-position of phenyl were the key point for the inhibitory activity.