# Structural Investigations on 2-Amidobenzimidazole Derivatives as New Inhibitors of Protein Kinase CK1 Delta

## TL;DR

This study explores new inhibitors of the CK1δ protein kinase, which is linked to diseases like cancer and Alzheimer's, and identifies promising compounds with strong inhibitory activity.

## Contribution

The paper introduces new 2-amidobenzimidazole derivatives as potent CK1δ inhibitors with nanomolar activity.

## Key findings

- Compounds with a (1H-pyrazol-3-yl)-acetyl group showed CK1δ inhibition in the low micromolar range.
- A 5-cyano substituent led to a compound with nanomolar potency (IC50 = 98.6 nM).
- Molecular docking and dynamics studies revealed key inhibitor–kinase interactions.

## Abstract

Protein kinase CK1δ (CK1δ) is a serine-threonine/kinase that modulates different physiological processes, including the cell cycle, DNA repair, and apoptosis. CK1δ overexpression, and the consequent hyperphosphorylation of specific proteins, can lead to sleep disorders, cancer, and neurodegenerative diseases. CK1δ inhibitors showed anticancer properties as well as neuroprotective effects in cellular and animal models of Parkinson’s and Alzheimer’s diseases and amyotrophic lateral sclerosis. To obtain new ATP-competitive CK1δ inhibitors, three sets of benzimidazole-2-amino derivatives were synthesized (1–32), bearing different substituents on the fused benzo ring (R) and diverse pyrazole-containing acyl moieties on the 2-amino group. The best-performing derivatives were those featuring the (1H-pyrazol-3-yl)-acetyl moiety on the benzimidazol-2-amino scaffold (13–32), which showed CK1δ inhibitor activity in the low micromolar range. Among the R substituents, 5-cyano was the most advantageous, leading to a compound endowed with nanomolar potency (23, IC50 = 98.6 nM). Molecular docking and dynamics studies were performed to point out the inhibitor–kinase interactions.