Coumarin bearing triazole hybrids as cholinesterase inhibitors targeting Alzheimer's disease

Abstract

A series of novel coumarin-triazole hybrids (12a–s) were synthesized and evaluated for their inhibitory activities against cholinesterase including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), enzymes related to Alzheimer's disease. The structure–activity relationship (SAR) analysis revealed that substitutions at the 2-position of the aromatic ring significantly enhanced anti-BChE potency, with compound 12c (2-fluorophenyl) exhibiting moderate activity with IC₅₀ = 4.37 ± 0.91 µM for BChE and 7.17 ± 0.42 µM for AChE. Docking studies demonstrated strong binding interactions of 12c with critical residues in the active site of the enzyme. Molecular dynamics simulations confirmed the stability of the 12c-AChE and 12c-BChE complexes over 100 ns, with low RMSD values and stable hydrogen bonding. These findings highlight the importance of electronic and steric effects in optimizing cholinesterase inhibition and provide insights into the design of effective agents for Alzheimer's disease therapy.