Development of coumarin-inspired bifunctional hybrids as a new class of anti-Alzheimer's agents with potent in vivo efficacy†

Considering the multifactorial and complex nature of Alzheimer's disease and the requirement of an optimum multifunctional anti-Alzheimer's agent, a series of triazole tethered coumarin–eugenol hybrid molecules was designed as potential multifunctional anti-Alzheimer's agents using donepezil and a template. The designed hybrid molecules were synthesized via a click chemistry approach and preliminarily screened for cholinesterase and Aβ_1–42 aggregation inhibition. Among them, AS15 emerged as a selective inhibitor of AChE (IC₅₀ = 0.047 μM) over butyrylcholinesterase (BuChE: IC₅₀ ≥ 10 μM) with desired Aβ_1–42 aggregation inhibition (72.21% at 50 μM) properties. In addition, AS15 showed protective effects against DNA damage caused by hydroxyl radicals originating from H₂O₂. Molecular docking and simulation studies confirmed the favorable interactions of AChE and the Aβ_1–42 monomer desired for their inhibition. AS15 exhibited an LD₅₀ value of 300 mg kg⁻¹ and showed significant improvements in memory and learning behavior in scopolamine-induced cognition impairment mouse-based animal models (Y-maze test and Morris water maze test) for behavioral analysis. Overall outcomes suggest AS15 as a potential preclinical multifunctional candidate for the management of Alzheimer's disease, and it serves as a promising lead for further development of potent and safer multifunctional anti-Alzheimer's agents.