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

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.