Triazole and Benzotriazole Derivatives as Novel Inhibitors for p90 Ribosomal S6 Protein Kinase 2: Synthesis, Molecular Docking and SAR Analysis

Abstract

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 IC 50 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.

Benzotriazole scaffold: An overview of antiproliferative potential, mechanisms of action, and structure–activity relationships

“…Both substituent groups lost their ability to inhibit RSK2 when electron‐withdrawing groups like NO 2 and Cl were used in their place. [ 63 ]…”

“…Both substituent groups lost their ability to inhibit RSK2 when electron-withdrawing groups like NO 2 and Cl were used in their place. [63] 2.7 | Benzotriazoles as CDKs and fms-like tyrosine kinase (FLT) inhibitors…”

Recent Development of Benzotriazole-based Medicinal Drugs

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The inhibition of kinases is one of the most important pathways to treat cancers attributing to the significant roles of kinases in cell multiplication [24]. The special structure of benzotriazole derivatives could readily bind with different kinases via multiple non-covalent forces such as hydrogen bonds, coordination, ion-dipole, cation-π, π-π stacking, hydrophobic effect and van der Waals force, thus effectively inhibiting the activity of various kinases including protein kinases CK2 and CHK1, histone deacetylases and focal adhesion kinase and so on.

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