Sharma_2023_ACS.Omega_8_11161

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 beta-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 beta-secretase-1 (BACE-1) with IC(50) values of 2.57, 3.26, and 10.65 microM, respectively. The hybrid, 10b, crosses the blood-brain barrier via passive diffusion and inhibits the self-aggregation of amyloid-beta 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.