Novel triazole-based coumarin compounds as acetylcholinesterase inhibitors: Evidence and mechanism of 3-acetyl coumarin tethered (2-bromophenyl)-1,2,3 triazole as a potential mixed type inhibitor

Acetylcholinesterase (AChE) inhibition remains an important therapeutic strategy for Alzheimer’s diseases, prompting immense research for novel and efficient small-molecule inhibitors. In this context, the present study describes the synthesis, characterization and evaluation of novel ether-linked 3-acetyl triazole-substituted coumarin derivatives as potential AChE inhibitors. The synthetic route involved 3-acetyl-7-hydroxycoumarin preparation through the reaction of 2,4-dihydoxybenzaldehyde with ethyl acetoacetate. Following alkylation at hydroxyl group, the acetylated 7-hydroxycoumarin underwent 1,3-dipolar cycloaddition i.e., Huisgen cycloaddition with various aromatic azides under sharpless click chemistry conditions, leading to the formation of a library of 16 novel coumarin tethered 1,2,3-triazole derivatives. Following synthesis and characterization using 1H NMR, 13C NMR and IR spectroscopy, the AChE inhibitory potential of the coumarin derivatives was assessed, yielding IC50 value in the range of 2.18 μM – 67.89 μM. Among them, compound 9 exhibited the most potent inhibition (IC50 = 2.18 μM), although lower than that of the standard inhibitor, eserine. Kinetic analysis indicated that compound 9 acted as a mixed-type inhibitor, with a Ki of 8.13 ± 0.18 μM. In silico simulation analysis elucidated the critical interactions between compound 9 and key AChE residues, including hydrogen bonding with Tyr121 and His444 and π-π stacking with Tyr334 and Trp283, supporting its strong binding affinity for the enzyme. Furthermore, the binding free energy calculations also confirmed the favourable thermodynamic interactions between the compound 9 and AChE. Collectively, the present findings highlight the therapeutic potential of compound 9 and establish this novel coumarin-triazole scaffold as a promising lead candidate for further optimization in development of AChE-targeted Alzheimer’s therapeutics.