LAUSR

Coumarin is a naturally occurring bioactive pharmacophore with wide occurrence among central nervous system (CNS)-active small molecules. 8-Acetylcoumarin, one of the natural coumarins, is a mild inhibitor of cholinesterases and β-secretase, which are vital targets of Alzheimer’s disease. Herein, we synthesized a series of coumarin–triazole hybrids as potential multitargeted drug ligands (MTDLs) with better activity profiles. The coumarin–triazole hybrids occupy the cholinesterase active site gorge from the peripheral to the catalytic anionic site. The most active analogue, 10b, belonging to the 8-acetylcoumarin core, inhibits acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase-1 (BACE-1) with IC50 values of 2.57, 3.26, and 10.65 μM, respectively. The hybrid, 10b, crosses the blood–brain barrier via passive diffusion and inhibits the self-aggregation of amyloid-β monomers. The molecular dynamic simulation study reveals the strong interaction of 10b with three enzymes and forming stable complexes. Overall, the results warrant a detailed preclinical investigation of the coumarin–triazole hybrids.