# Investigating the Ligand‐Binding Properties of N‐arylbenzimidazoles as Novel Elastase Inhibitors

## TL;DR

Scientists designed new compounds that inhibit elastase, an enzyme linked to skin elasticity, and found one with strong inhibitory effects.

## Contribution

A novel series of N-arylbenzimidazoles is developed and tested as potent, reversible elastase inhibitors.

## Key findings

- Compound 7 shows potent antielastase activity with an IC50 of 41.1 µM.
- Molecular docking and dynamic studies validate the structure–activity relationship.
- The inhibition mechanism is competitive, preserving other serine protease functions.

## Abstract

Human elastase 1 has been shown to possess an important role in maintaining skin stability and elasticity through the proteolytic cleavage of elastin (ELN), a hydrophobic protein that serves as a key component of extracellular matrix in the skin. The development of antielastase agents represents a promising therapeutic approach for treating skin pathologies characterized by elastin degradation, with applications in both dermatology and cosmetology. Reversible inhibitors represent a therapeutic strategy, offering selective inhibition of elastase proteolytic activity while preserving the function of other physiologically essential serine proteases. Using porcine pancreatic elastase (PPE) as a well‐established surrogate of human skin elastase, a focused series of noncovalent inhibitors designed to bind the catalytic area of PPE is assayed. Several compounds display an antielastase activity, including N‐(2‐bromophenyl)‐2‐(6‐chloro‐1‐(3,5‐dimethylbenzyl)‐1H‐benzo[d]imidazol‐2‐ylthio)acetamide (7) that exhibits the most potent inhibitory effects (IC50 = 41.1 µM), similar to standard compound oleanolic acid (IC50 value of 25.7 µM). The observed structure–activity relationship is further validated through molecular docking and dynamic studies, which provide mechanistic understanding of the binding interactions and establish suggestions for further rational drug design.

A series of novel N‐[(3,5‐dimethylphenyl)methyl]‐1H‐benzimidazole derivatives is designed, synthesized, and evaluated for inhibitory activity against elastase. Several compounds demonstrate an antielastase activity, including the N‐(2‐bromophenyl)‐2‐(6‐chloro‐1‐(3,5‐dimethylbenzyl)‐1H‐benzo[d]imidazol‐2‐ylthio)acetamide, showing the greatest potency (IC50 = 41.1 µM) through a competitive inhibition mechanism. Computational analyses elucidate the binding modes of these derivatives and provide valuable insights to guide future rational drug design efforts.© 2026 WILEY‐VCH GmbH