Design and one-pot synthesis of new 1,4-disubstituted 1,2,3-triazoles: acetylcholinesterase inhibitory activity and in silico studies.

Abstract

In this study, two novel 1,2,3-triazole derivatives was designed and synthesized from 1-(4-(bromomethyl)phenyl)-3,5-dimethyladamantane precursors via reactions with sodium azide and terminal alkynes. The synthesized compounds were evaluated for their anticholinesterase potential and compared with standard reference inhibitors, showing moderate to excellent inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among them, 3a emerged as the most potent dual inhibitor, with IC₅₀ values of 8.56 ± 1.17 μM (AChE) and 13.27 ± 1.20 μM (BuChE). To further elucidate their behavior, a comparative theoretical and experimental investigation of 3a and 3b was performed using frontier molecular orbital, quantum descriptor, ESP, IR, and TD-DFT analyses, which revealed distinct electronic and conformational features influencing their biological interactions. Molecular docking confirmed stronger binding and inhibitory activity of 3a toward both enzymes, while ADMET predictions highlighted its CNS drug-likeness. These integrated findings underscore the potential of adamantane-based triazoles as promising scaffolds for the design of novel cholinesterase inhibitors.