|
Abstract
|
A novel adamantane-containing lidocaine derivative was synthesized using the Add-on strategy to enhance the biostability and prolong the duration of action of the parent lidocaine molecule. The two-step synthesis commenced with the acylation of 2,6-dimethylaniline with chloroacetyl chloride in glacial acetic acid at 0–5 °C, yielding the intermediate 2-chloro-N-(2,6-dimethylphenyl)acetamide. In the second step, the chloroamide intermediate underwent nucleophilic substitution with 1-aminoadamantane via reflux in toluene at 105 °C for 72 hours, successfully yielding the target derivative, N-(2,6-dimethylphenyl)-2-(1-adamantyl)acetamide, with high yield. The final structure was comprehensively confirmed using FT-IR, 1H NMR, and 13C NMR spectroscopy. In vitro stability results using the trypsin inhibition assay revealed that the adamantane derivative exhibited 60% inhibition of enzyme activity, compared to 49% inhibition shown by the parent lidocaine. This sim 11% increase in enzymatic resistance strongly supports the role of the bulky adamantane group as a steric metabolic shield, protecting the adjacent amide bond from enzymatic degradation. These findings demonstrate the high potential of this derivative for developing a new generation of local anesthetics with significantly prolonged duration of action.
|